Heteroaryl compounds and their use

ABSTRACT

The application is directed to compounds of formula (I): and their salts and solvates, wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , and n are as set forth in the specification, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of a lysosomal storage disease, such as Gaucher&#39;s, and other diseases or disorders that are synucleinopathies.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to European Application No.EP16382672.0, filed on Dec. 29, 2016, the entirety of which isincorporated by reference herein.

FIELD OF THE DISCLOSURE

The present disclosure is related to heteroaryl compounds, andespecially pyridyl, pyrimidinyl, and triazinyl compounds, new processesfor their preparation, and the use of the heteroaryl compounds in thetreatment and/or prevention of lysosomal storage disorders in a patient,such as Gaucher's disease. The present disclosure is also related to theuse of the heteroaryl compounds described herein in the treatment and/orprevention of other medical disorders in a patient, such as, forexample, Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, or multiple myeloma.

BACKGROUND OF THE DISCLOSURE

Gaucher's disease, suggested to arise from β-glucocerebrosidase enzymedeficiency, is very rare lysosomal storage disease. Said conditionassociated with β-glucocerebrosidase is known to be caused by adeficiency of the enzyme β-glucocerebrosidase due to mutations in thegene.

β-Glucocerebrosidase cleaves β-glucocerebroside from differentsubstrates, and deficiencies in its activity cause said substrates(i.e., gangliosides, and oligosaccharides carrying terminal β-linkedglucocerebroside) to accumulate in patients suffering from conditionsassociated with β-glucocerebrosidase activity, such as Gaucher'sdisease. Beutler et al. (Mol Med. 1(1):82-92 (1994)) reported thatdeficiency of glucocerebrosidase leads to accumulation of insolubleglucocerebrosides in the tissues, resulting in the clinicalmanifestations of Gaucher's disease.

In many lysosomal disorders, like Gaucher's disease, the mutant enzymesoften retain catalytic activity but fold improperly in the endoplasmicreticulum (“ER”). This triggers ER accumulation of the mutant protein,which is eventually tagged for proteasome degradation by ubiquitination,avoiding the transport of the enzyme to the lysosome. See, e.g., Patniaket al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012).

Gaucher's (or Gaucher) disease is a heterogenous disorder having threesubtypes. The majority of patients, those without neurologicmanifestations of the disease, are classified as type I. In type I,clinical manifestations include enlarged spleen and liver, plateletdeficiency, anemia, and bone disease. Types II and III are neuronopathicforms, classified with respect to severity and to the time of onset ofneurologic disease. Type II is most severe with symptoms at or near thetime of birth. Patients with type II have a median life span of 9months. Type III has a later onset. See, e.g., Patniak et al., Journalof Medicinal Chemistry 55(12):5734-5748 (2012). Patients with Gaucher'sdisease exhibit hematological manifestations, such as anemia andthrombocytopenia, as well as hepatosplenomegaly, skeletal deformities,and in some cases, neurological impairment. See, e.g., Boyd et al.,Journal of Medicinal Chemistry 56 (7):2705-2725 (2013).

Enzyme replacement therapy (“ERT”) and substrate inhibition therapy(“SRT”) are two current therapies for type I Gaucher's disease. ERTinvolves long term treatment via injection of a recombinant enzyme(imiglucerase) into patients. While ERT may be effective in reducing andreversing the clinical symptoms of the disease, it is very costly. SRTis generally indicated for the treatment of adult patients with mild tomoderate type I Gaucher's disease for whom ERT is not a therapeuticoption. The prescribed drug, an iminosugar miglustat, inhibitsglucosylceramide synthetase, reducing the production ofglucocerebrosides in the lysosome. While SRT may be effective for somepatients, it is associated with side effects, including weight loss,diarrhea, tremors, and peripheral nerve damage. Neither ERT nor SRT areeffective against the neuronopathic types II and III of Gaucher'sdisease. See, e.g., Patniak et al., Journal of Medicinal Chemistry55(12):5734-5748 (2012).

Mutations in the gene encoding glucocerebrosidase are also a risk factorfor synucleinopathies, such as Parkinson's disease and diffuse Lewy Bodydisease. Parkinson's disease is a degenerative disorder of the centralnervous system associated with death of dopamine-containing cells in aregion of the midbrain. Diffuse Lewy Body disease is a dementia that issometimes confused with Alzheimer's disease.

Small molecules capable of binding allosterically or competitively tomutated β-glucocerebrosidase enzyme, thereby stabilizing the enzymeagainst degradation (chaperones), constitute an important therapeutictarget in conditions associated with the alteration of the activity ofβ-glucocerebrosidase. By binding and stabilizing mutant proteins, thesechemical chaperones facilitate protein folding and eventually increasetheir transport to the lysosome. Improved trafficking of the mutantprotein from the ER to the lysosome results in the reduction of lysosomesize and correction of the storage. These chaperones may also increasethe stability of mutant enzymes toward degradation in the lysosome. See,e.g., Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748(2012).

It has been surprisingly found that compounds of formula (I) are capableof binding to β-glucocerebrosidase thereby stabilizing the enzymeagainst denaturation.

BRIEF SUMMARY OF THE DISCLOSURE

The present disclosure is related to the discovery that heteroarylcompounds represented by formula (I) are capable of binding to mutatedβ-glucocerebrosidase and are thus useful in the treatment or preventionof a lysosomal storage disease, such as Gaucher's disease.

The present disclosure provides a method of treating or preventing alysosomal storage disease, such as Gaucher's disease, in a patient inneed thereof by administering an effective amount of a compound offormula (I), or a salt or solvate thereof, as described herein.Compounds represented by formula (I) and the salts and solvates thereof,are herein collectively referred to as “Compounds of the Disclosure”(each individually referred to as a “Compound of the Disclosure”).

In another aspect, the present method of treating a lysosomal storagedisease, such as Gaucher's disease, further comprises administering tothe patient at least one other therapeutic agent. In one embodiment, thetherapeutic agent is an effective amount of an enzyme for enzymereplacement therapy. In another embodiment, the enzyme isβ-glucocerebrosidase or an analog thereof. In another embodiment, theenzyme is imiglucerase.

In another aspect, the method further comprises administering to thepatient an effective amount of a small molecule chaperone. In anotherembodiment, the small molecule chaperone binds competitively to anenzyme. In another embodiment, the small molecule chaperone is selectedfrom the group consisting of iminoalditols, iminosugars, aminosugars,thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase,phosphatase, and peptidase inhibitors. In another embodiment, the smallmolecule chaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), andambroxol. In another embodiment, the small molecule chaperone ismiglustat.

In another embodiment, the therapeutic agent is an effective amount ofsubstrate reduction agent for substrate reduction therapy. In anotherembodiment, the substrate reduction agent is miglustat.

The present disclosure is also directed to the use of a compound offormula (I), or a salt or solvate thereof, as described herein, for thetreatment or prevention of a lysosomal storage disease, such asGaucher's disease.

A number of compounds useful in the treatment or prevention of thepresent disclosure have not been hereto for reported. Thus, one aspectof the present disclosure is directed to the novel compounds of formula(I), and the salts and solvates thereof. Another aspect of the presentdisclosure is directed to pharmaceutical compositions comprising thesenovel compounds of formula (I), and the salts and solvates thereof, andat least one pharmaceutically acceptable excipient.

In one aspect, the present disclosure provides compounds of formula (I),and the salts and solvates thereof, with the proviso that no more thantwo of A¹, A², or A³ is N.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, and at least onepharmaceutically acceptable excipient.

In another aspect, the present disclosure provides compounds of formula(I) as defined herein, and the pharmaceutically acceptable salts andsolvates thereof, for use as a medicament.

In another aspect, the present disclosure provides compounds of formula(I) as defined herein, and the pharmaceutically acceptable salts andsolvates thereof, for use in the prevention or treatment of a lysosomalstorage disease, such as Gaucher's disease.

In another aspect, the present disclosure provides use of a compound offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, as defined herein, in the preparation of a medicament for theprevention or treatment of a lysosomal storage disease, such asGaucher's disease.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, and at least onepharmaceutically acceptable excipient, for use in the treatment orprevention of a lysosomal storage disease, such as Gaucher's disease.

In another aspect, the present disclosure is directed to method oftreating or preventing a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma,comprising administering to a patient in need thereof an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof. In one embodiment, the method further comprisesadministering to the patient at least one other therapeutic agent. Inanother embodiment, the therapeutic agent is an effective amount of anenzyme for enzyme replacement therapy. In another embodiment, the enzymeis β-glucocerebrosidase or an analog thereof. In another embodiment, theenzyme is imiglucerase. In another embodiment, the therapeutic agent isan effective amount of a small molecule chaperone. In anotherembodiment, the small molecule chaperone binds competitively to anenzyme. In another embodiment, the small molecule chaperone is selectedfrom the group consisting of iminoalditols, iminosugars, aminosugars,thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase,phosphatase, and peptidase inhibitors. In another embodiment, the smallmolecule chaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), andambroxol. In another embodiment, the small molecule chaperone ismiglustat.

In another aspect, the present disclosure is directed to a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for use in treating or preventing a disease or disorder selected fromthe group consisting of Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycyctic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis, andmultiple myeloma, in a patient. In one embodiment, the compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,is administered to the patient in combination with at least one othertherapeutic agent. In another embodiment, the therapeutic agent is aneffective amount of an enzyme for enzyme replacement therapy. In anotherembodiment, the enzyme is β-glucocerebrosidase or an analog thereof. Inanother embodiment, the enzyme is imiglucerase. In another embodiment,the therapeutic agent is an effective amount of a small moleculechaperone. In another embodiment, the small molecule chaperone bindscompetitively to an enzyme. In another embodiment, the small moleculechaperone is selected from the group consisting of iminoalditols,iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase,glycosyl transferase, phosphatase, and peptidase inhibitors. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat. In another embodiment, the small moleculechaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In anotherembodiment, the small molecule chaperone is miglustat.

In another aspect, the present disclosure is directed to a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for use in the treatment or prevention of a disease or disorder selectedfrom the group consisting of Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycyctic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis, andmultiple myeloma in a patient in need of such treatment or prevention.

In another aspect, the present disclosure is also directed to the use ofa compound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, in the manufacture of a medicament for treating and/orpreventing a disease or disorder selected from the group consisting ofParkinson's disease, Lewy body disease, dementia, multiple systematrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder,major depression, polycyctic kidney disease, type 2 diabetes, open angleglaucoma, multiple sclerosis, and multiple myeloma in a patient in needof such treatment or prevention.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, and at least onepharmaceutically acceptable excipient, for use in the treatment orprevention of a disease or disorder selected from the group consistingof Parkinson's disease, Lewy body disease, dementia, multiple systematrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder,major depression, polycyctic kidney disease, type 2 diabetes, open angleglaucoma, multiple sclerosis, and multiple myeloma.

Other aspects and advantages of the disclosure will be readily apparentfrom the following detailed description of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the disclosure as claimed.

DETAILED DESCRIPTION OF THE DISCLOSURE

One aspect of the disclosure is based on the use of Compounds of theDisclosure for binding to mutated β-glucocerebrosidase. In view of thisproperty, Compounds of the Disclosure are expected to be useful fortreating or preventing Gaucher's disease.

Compounds of the Disclosure useful in this aspect of the disclosure arecompounds of formula (I):

and the pharmaceutically acceptable salts and solvates thereof, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independently selected from the group consisting of halogen,—C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN;

n is 1 or 2, wherein the alkylene chain can be optionally substitutedwith one or more —C₁₋₄ alkyl groups;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,and optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and

R² is selected from the group consisting of hydrogen, —C₁₋₄ alkyl, andC₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl is optionally substituted with—O(C₁₋₄)alkyl optionally substituted with —O(C₁₋₄)NH₂, hydroxy, —CN,halogen, or —N(Rb)₂; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,and —C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein saidalkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkylor heterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and

R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.

In another embodiment, Compounds of the Disclosure useful in this aspectof the disclosure are compounds of formula (I):

and the pharmaceutically acceptable salts and solvates thereof, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independently selected from the group consisting of halogen,—C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or —C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,and —C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein saidalkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkylor heterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl and heteroaryl groups are optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein A¹, A² and A³ are N.

In another aspect, useful Compounds of the Disclosure include compoundsof formula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R¹, R², R³, n, A¹, A², and A³ are as described above,with the proviso that no more than two of A¹, A², or A³ is N.

In another embodiment of this aspect of the disclosure, Compounds of theDisclosure are compounds of formula (I), and the pharmaceuticallyacceptable salts and solvates thereof, wherein A¹ is N and A² and A³ areeach independently selected from the group consisting of CH and C(R⁴).In another embodiment, A² and A³ are both CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and their pharmaceutically acceptable salts and solvatesthereof, wherein A² is N and A¹ and A³ are each independently selectedfrom the group consisting of CH and C(R⁴). In another embodiment, A¹ andA³ are both CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein A³ is N and A¹ and A² are each independently selectedfrom the group consisting of CH and C(R⁴). In another embodiment, A¹ andA² are both CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein A¹ and A² are both N and A³ is CH or C(R⁴). In anotherembodiment, A³ is CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein A¹ and A³ are both N and A² is CH or C(R⁴). In anotherembodiment, A² is CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein A² and A³ are both N and A¹ is CH or C(R⁴). In anotherembodiment, A¹ is CH.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein n is 1.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein n is 2.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R³ is —C₆₋₁₀ aryl optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.In another embodiment, R³ is unsubstituted —C₆₋₁₀ aryl or —C₆₋₁₀ arylsubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl,—S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —O(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). In one embodiment, R³ isunsubstituted —C₆₋₁₀ aryl, and preferably unsubstituted phenyl. Inanother embodiment, R³ is —C₆₋₁₀ aryl substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂,—NH(C₁₋₄ alkyl), and —C₁₋₄ alkyl optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting ofhalogen, —CN, —O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). Inanother embodiment, R³ is —C₆₋₁₀ aryl, and preferably phenyl,substituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, methoxy, ethoxy,methylthio, ethylthio, dimethylamino, diethylamino, methylamino,ethylamino, halomethyl (such as fluoromethyl), di(halo)methyl (such asdifluoromethyl), tri(halo)methyl (such as trifluoromethyl), cyanomethyl,methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl,methylaminomethyl, and methylaminoethyl. In another embodiment, R³ isphenyl substituted with halogen, hydroxy, —CN, methyl, ethyl, methoxy,or ethoxy. In one embodiment, the substituent is attached to themeta-position of the phenyl group. In another embodiment, thesubstituent is attached to the ortho-position of the phenyl group. Inanother embodiment, the substituent is attached to the para-position ofthe phenyl group.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R³ is -(5- or 10-membered)-C₁₋₉ heteroaryl optionallysubstituted with 1, 2 or 3 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂,—C₁₋₄alkyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, —CN, —ORb,and —N(Rb)₂, optionally substituted —C₆₋₁₀ aryl, optionally substituted-(5- to 10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉heterocyclyl. In one embodiment, R³ is unsubstituted -(5- or10-membered)-C₁₋₉ heteroaryl or -(5- or 10-membered)-C₁₋₉ heteroarylsubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl,—S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —O(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). In another embodiment, R³ isunsubstituted -(5- or 10-membered)-C₁₋₉ heteroaryl. In anotherembodiment, R³ is -(5- or 10-membered)-C₁₋₉ heteroaryl substituted with1 or 2 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyl optionally substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of halogen, —CN, —O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄alkyl).

In another embodiment, R³ is —C₃₋₁₀ cycloalkyl or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said cycloalkyl and heterocyclylgroups are optionally substituted with 1, 2 or 3 substituents eachindependently selected from the group consisting of halogen, hydroxy,—CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionally substituted with 1, 2,or 3 substituents each independently selected from the group consistingof halogen, —CN, —ORb, and —N(Rb)₂, optionally substituted —C₆₋₁₀ aryl,optionally substituted -(5- to 10-membered)-C₁₋₉ heteroaryl and -(5- to10-membered)-C₂₋₉ heterocyclyl.

In another embodiment, R³ is selected from the group consisting of—C₆₋₁₀ aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl,and -(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said aryl,heteroaryl, cycloalkyl, and heterocyclyl groups are optionallysubstituted with 1, 2 or 3 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂,—C₁₋₄alkyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, —CN, —ORb,and —N(Rb)₂, optionally substituted —C₆₋₁₀ aryl, optionally substituted-(5- to 10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉heterocyclyl, and wherein said aryl, heteroaryl, cycloalkyl, andheterocyclyl is optionally fused with a cycloalkyl or heterocyclyl togive a bicyclic ring system, e.g.,

and said cycloalkyl or heterocyclyl is optionally fused with an aryl orheteroaryl to give a bicyclic ring system. e.g.,

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R is H and R is as defined above.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R² is —C₁₋₄ alkyl and R¹ is as defined above. Inanother embodiment, R² is methyl or ethyl. In another embodiment, R² ismethyl.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R¹ is —C₆₋₁₀ aryl or —C₁₋₄ alkyl-C₆₋₁₀ aryl, whereinsaid aryl or alkylaryl is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyl optionallysubstituted with 1, 2, or 3 halogen atoms, optionally substituted —C₆₋₁₀aryl, optionally substituted -(5- to 10-membered)-C₁₋₉ heteroaryl, and-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein Rb is as defined above.

In one embodiment, R¹ is unsubstituted C₆₋₁₀ aryl optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —ORb, and —N(Rb)₂,optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.In one embodiment, R¹ is unsubstituted —C₆₋₁₀ aryl or —C₆₋₁₀ arylsubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl,—S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —O(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). In another embodiment, R¹ isunsubstituted —C₆₋₁₀ aryl, and preferably unsubstituted phenyl. Inanother embodiment, R¹ is —C₆₋₁₀ aryl substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂,—NH(C₁₋₄ alkyl), and —C₁₋₄ alkyl optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting ofhalogen, —CN, —O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). Inanother embodiment, R¹ is —C₆₋₁₀ aryl, and preferably phenyl,substituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, methoxy, ethoxy,methylthio, ethylthio, dimethylamino, diethylamino, methylamino,ethylamino, halomethyl (such as fluoromethyl), di(halo)methyl (such asdifluoromethyl), tri(halo)methyl (such as trifluoromethyl), cyanomethyl,methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl,methylaminomethyl, and methylaminoethyl. In another embodiment, R¹ isphenyl substituted with halogen, hydroxy, —CN, methyl, ethyl, methoxy,or ethoxy. In one embodiment, the substituent is attached to themeta-position of the phenyl group. In another embodiment, thesubstituent is attached to the ortho-position of the phenyl group. Inanother embodiment, the substituent is attached to the para-position ofthe phenyl group.

In another embodiment, R¹ is unsubstituted —C₁₋₄ alkyl-C₆₋₁₀ aryl or—C₁₋₄ alkyl-C₆₋₁₀ aryl optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.In one embodiment, R¹ is unsubstituted —C₁₋₄ alkyl-C₆₋₁₀ aryl or —C₁₋₄alkyl-C₆₋₁₀ aryl substituted with 1 or 2 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN,—O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and—C₁₋₄ alkyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, —CN,—O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). In one embodiment,R¹ is unsubstituted —C₁₋₄ alkyl-C₆₋₁₀ aryl, and preferably unsubstitutedbenzyl or phenethyl. In another embodiment, R¹ is —C₁₋₄ alkyl-C₆₋₁₀ arylsubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl,—S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, CN, —O(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl). In another embodiment, R¹ is —C₁₋₄alkyl-C₆₋₁₀ aryl, and preferably benzyl, substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, methoxy, ethoxy, methylthio, ethylthio,dimethylamino, diethylamino, methylamino, ethylamino, halomethyl (suchas fluoromethyl), di(halo)methyl (such as difluoromethyl),tri(halo)methyl (such as trifluoromethyl), cyanomethyl, methoxymethyl,methoxyethyl, dimethylaminomethyl, dimethylaminoethyl,methylaminomethyl, and methylaminoethyl. In another embodiment, R¹ isbenzyl substituted with halogen, hydroxy, —CN, methyl, ethyl, methoxy,or ethoxy. In one embodiment, the substituent is attached to themeta-position of the phenyl group. In another embodiment, thesubstituent is attached to the ortho-position of the phenyl group. Inanother embodiment, the substituent is attached to the para-position ofthe phenyl group.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein Rb is hydrogen or —C₁₋₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R¹ and R² together with the nitrogen atom to which theyare attached form an optionally substituted 5- to 10-memberedheterocyclic ring, wherein said heterocyclic ring optionally contains 1,2, or 3 additional heteroatoms selected from the group consisting of N,S, or O, and wherein said heterocyclic ring is optionally fused to aphenyl ring. In another embodiment, R¹ and R² together with the nitrogenatom form a morpholinyl ring. In another embodiment, R¹ and R² togetherwith the nitrogen atom form a piperidinyl ring optionally substituted atthe nitrogen with —C₁₋₄ alkyl (such as methyl or ethyl), —C₆₋₁₀ aryl(such as phenyl) optionally substituted with C₁₋₄ alkyl or —O(C₁₋₄alkyl), or —C(═O)O(C₁₋₄ alkyl).

In another embodiment, Compounds of the Disclosure are compounds offormula (I), and the pharmaceutically acceptable salts and solvatesthereof, wherein R¹ and R² together with the nitrogen atom to which theyare attached form a 5- or 6-membered ring optionally fused to a phenylring.

In another embodiment, the present disclosure provides a Compound of theDisclosure selected from the group consisting of

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the present disclosure provides a Compound of theDisclosure selected from the group consisting of

and the pharmaceutically acceptable salts thereof.

In another embodiment, the present disclosure provides a Compound of theDisclosure selected from the group consisting of

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the present disclosure provides a Compound of theDisclosure selected from the group consisting of

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the present disclosure provides a Compound of theDisclosure selected from the group consisting of

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure that may be employedin the method of the present disclosure include:

and the pharmaceutically acceptable salts and solvates thereof.

In another embodiment, Compounds of the Disclosure that may be employedin the method of the present disclosure include:

and the pharmaceutically acceptable salts and solvates thereof.

As used herein, the terms “halogen” or “halo” refer to —F, —Cl, —Br, or—I.

As used herein, the term “hydroxyl” or “hydroxy” refers to the group—OH.

As used herein, the term “alkyl” refers to a linear or branchedhydrocarbon chain radical consisting of carbon and hydrogen atoms,containing no unsaturation, which is attached to the rest of themolecule by a single bond and, unless otherwise specified, an alkylradical typically has from 1 to 4 carbon atoms, i.e., C₁₋₄ alkyl.Exemplary C₁₋₄ alkyl groups can be methyl, ethyl, n-propyl, i-propyl,n-butyl, tert-butyl, i-butyl and sec-butyl. In another embodiment, thealkyl is C₁₋₂ alkyl (methyl or ethyl).

As used herein, the term “C₁₋₄ alkoxy” refers to oxygen substituted byone of the C₁₋₄ alkyl groups mentioned above (e.g., methoxy, ethoxy,propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, and sec-butoxy),for example by one of the C₁₋₂ alkyl groups. butoxy, iso-butoxy, andsec-butoxy), for example by one of the C₁₋₂ alkyl groups.

As used herein, the term “cycloalkyl” embraces saturated carbocyclicradicals and, unless otherwise specified, a cycloalkyl radical typicallyhas from 3 to 6 carbon atoms. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. It is,for example, cyclopropyl, cyclopentyl and cyclohexyl. In anotherembodiment, the cycloalkyl group is C₃₋₁₀ cycloalkyl.

As used herein, the term “alkylcycloalkyl” when employed in thedefinition of a substituent refers to a cycloalkyl group as definedabove which is linked through an alkylene radical, such as C₁₋₄alkylene, with the core structure which it substitutes. As an example, acyclopentylethyl substituent is a substituent consisting of acyclopentyl group linked through an ethylene group to the core structurewhich it substitutes.

As used herein, the terms “heterocyclyl” or “heterocyclic group” embracetypically a monocyclic or polycyclic, non-aromatic, saturated orunsaturated C₂₋₁₀ carbocyclic ring, such as a 5- to 10-membered radical,in which one or more, for example 1, 2, 3 or 4 of the carbon atoms, forexample, 1 or 2 of the carbon atoms are replaced by a heteroatomselected from N, O and S. In one embodiment, the heterocyclyl is a C₃₋₇heterocyclyl, i.e., a heterocycle having 3-7 carbon atoms and at leastone heteroatom. In another embodiment, a heterocyclyl is a (5- to10-membered)-C₂₋₉ heterocyclyl, i.e., a heterocycle having 5- to10-members, of which 2-9 members are carbon. In another embodiment, theheteroatom is N. In another embodiment, the heteroatom is O.

In another embodiment, the heterocyclyl radicals are saturated. Aheterocyclic radical can be a single ring or two or more fused ringswherein at least one ring contains a heteroatom. When a heterocyclylradical carries one or more substituents, the substituents can be thesame or different.

A said optionally substituted heterocyclyl is typically unsubstituted orsubstituted with 1, 2 or 3 substituents which can be the same ordifferent. Examples of heterocyclic radicals include piperidyl,pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, cromanyl,isocromanyl, imidazolidinyl, oxiranyl, azaridinyl, 4,5-dihydro-oxazolyland 3-aza-tetrahydrofuranyl. The substituents are, for example, selectedfrom halogen atoms, for example, fluorine or chlorine atoms, hydroxygroups, alkoxycarbonyl groups in which the alkyl moiety has from 1 to 4carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups,cyano groups, C₁₋₄ alkyl groups optionally substituted by one or morehalogen atoms, C₁₋₄ alkoxy groups, optionally substituted by one or morehalogen atoms and C₁₋₄ hydroxyalkyl groups.

As used herein, the term “alkylheterocyclyl” when employed in thedefinition of a substituent refers to a heterocyclyl group as definedabove which is linked through an alkylene radical with the corestructure which it substitutes. In one embodiment, the alkylheterocyclylis a —C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl.

As used herein, the term “aryl” designates typically a C₆₋₁₀ monocyclicor polycyclic aryl radical such as phenyl and naphthyl. In anotherembodiment, the aryl is phenyl. A said optionally substituted arylradical is typically unsubstituted or substituted with 1, 2 or 3substituents which can be the same or different. The substituents are,for example, selected from halogen atoms, for example, fluorine orchlorine atoms, hydroxy groups, alkoxycarbonyl groups in which the alkylmoiety has from 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoylgroups, nitro groups, cyano groups, C₁₋₄ alkyl groups optionallysubstituted by one or more halogen atoms, C₁₋₄ alkoxy groups, optionallysubstituted by one or more halogen atoms and C₁₋₄ hydroxyalkyl groups.When an aryl radical carries 2 or more substituents, the substituentscan be the same or different. Unless otherwise specified, thesubstituents on an aryl group are typically themselves unsubstituted.

As used herein, the term “alkylaryl” when employed in the definition ofa substituent refers to an aryl group as defined above which is linkedthrough an alkylene radical, such as C₁₋₄ alkylene, with the corestructure which it substitutes.

As used herein, the term “heteroaryl” designates typically a 5- to10-membered ring system, comprising at least one heteroaromatic ring andcontaining at least one heteroatom selected from O, S and N, typically1, 2, 3, or 4 heteroatoms.

A heteroaryl group can comprise a single ring or two or more fused ringswherein at least one ring contains a heteroatom. A said optionallysubstituted heteroaryl group is typically unsubstituted or substitutedwith 1, 2 or 3 substituents which can be the same or different. Thesubstituents are, for example, selected from halogen atoms, for example,fluorine, chlorine or bromine atoms, alkoxycarbonyl groups in which thealkyl moiety has from 1 to 4 carbon atoms, carbamoyl groups, nitrogroups, hydroxy groups, C₁₋₄ alkyl groups, optionally substituted by oneor more halogen atoms and C₁₋₄ alkoxy groups, optionally substituted byone or more halogen atoms. When a heteroaryl radical carries 2 or moresubstituents, the substituents can be the same or different. Unlessotherwise specified, the substituents on a heteroaryl radical aretypically themselves unsubstituted.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, furyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl,isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl,indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl,indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl,pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl,1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, and the variouspyrrolopyridyl radicals.

In another embodiment, the heteroaryl is a (5- to 10-membered)-C₂₋₉heteroaryl. In another embodiment, the heteroaryl is optionallysubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted C₆₋₁₀ aryl, optionally substituted (5- to 10-membered)-C₁₋₉heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl; said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl, and alkylheterocyclyl is optionally fused to a further(second) ring.

The mention of optionally substituted heteroaryl radicals or restswithin the present disclosure is intended to cover the N-oxidesobtainable from these radicals when they comprise N-atoms.

As used herein, the term “alkylheteroaryl” when employed in thedefinition of a substituent refers to an heteroaryl group as definedabove which is linked through an alkylene radical with the corestructure which it substitutes. In another embodiment, thealkylheteroaryl is a —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉ heteroaryl.

The term “pharmaceutically acceptable” refers to compositions andmolecular entities that are physiologically tolerable and do nottypically produce an allergic reaction or a similar unfavorablereaction, such as gastric disorders, dizziness and suchlike, whenadministered to a human or animal. For example, the term“pharmaceutically acceptable” means it is approved by a regulatoryagency of a state or federal government or is included in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

The term “treatment” or “treating” refers to administering a therapy inan amount, manner or mode effective to improve a condition, symptom, orparameter associated with a condition or to prevent progression of acondition, to either a statistically significant degree or to a degreedetectable to one skilled in the art. An effective amount, manner, ormode can vary depending on the subject and can be tailored to thepatient.

The term “about”, as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and precision of themeasuring equipment. Typically, the term “about” includes the recitednumber±10%. Thus, “about 10” means 9 to 11.

As used herein, the term “optionally substituted” refers to a group thatcan be unsubstituted or substituted.

The term “solvate” means any form of the active compound of thedisclosure which has another molecule (for example a polar solvent suchas water or ethanol, a cyclodextrin or a dendrimer) attached to itthrough noncovalent bonds. Methods of solvation are known within theart.

The disclosure also provides salts of the Compounds of the Disclosure.Non-limiting examples are sulphates; hydrohalide salts; phosphates;lower alkane sulphonates; arylsulphonates; salts of C₁₋₂₀ aliphaticmono-, di- or tribasic acids which can contain one or more double bonds,an aryl nucleus or other functional groups such as hydroxy, amino, orketo; salts of aromatic acids in which the aromatic nuclei may or maynot be substituted with groups such as hydroxyl, lower alkoxyl, amino,mono- or di-lower alkylamino sulphonamido. Also included within thescope of the disclosure are quaternary salts of the tertiary nitrogenatom with lower alkyl halides or sulphates, and oxygenated derivativesof the tertiary nitrogen atom, such as the N-oxides. In preparing dosageformulations, those skilled in the art will select the pharmaceuticallyacceptable salts.

Solvates and salts can be prepared by methods known in the state of theart. Note that the non-pharmaceutically acceptable solvates also fallwithin the scope of the disclosure because they can be useful inpreparing pharmaceutically acceptable salts and solvates.

The Compounds of the Disclosure also seek to include compounds thatdiffer only in the presence of one or more isotopically enriched atoms.For example, compounds having the present structures except for thereplacement of a hydrogen by a deuterium or tritium, or the replacementof a carbon by a carbon enriched in ¹¹C, ¹³C or ¹⁴C or the replacementof a nitrogen by a ¹⁵N enriched nitrogen are within the scope of thisdisclosure.

Some of the compounds disclosed herein can contain one or moreasymmetric centers and can thus give rise to enantiomers, diastereomers,and other stereoisomeric forms, such as epimers. The present disclosureis meant to encompass the uses of all such possible forms, as well astheir racemic and resolved forms and mixtures thereof. The individualenantiomers can be separated according to methods known to those ofordinary skill in the art in view of the present disclosure. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that they include both E and Z geometric isomers. All tautomersare intended to be encompassed by the present disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “epimer” refers to diastereomers that have oppositeconfiguration at only one of two or more tetrahedral streogenic centerspresent in the respective molecular entities.

The term “stereogenic center” is an atom, bearing groups such that aninterchanging of any two groups leads to a stereoisomer.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

Some reactions for preparing Compounds of the Disclosure involveemploying amino protecting groups. As used herein, an “amine protectinggroup” or “amino protecting group” refers to a group that blocks (i.e.,protects) the amine functionality while reactions are carried out onother functional groups or parts of the molecule. Those skilled in theart will be familiar with the selection, attachment, and cleavage ofamine protecting groups and will appreciate that many differentprotective groups are know in the art, the suitability of one protectivegroup or another being dependent on the particular synthetic schemeplanned. Treatises on the subject are available for consultation, suchas Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups in OrganicSynthesis, 4rd Ed. (J. Wiley & Sons, 2007), herein incorporated byreference in its entirety. Suitable amine protecting groups includemethyl carbamate, tert-butyloxycarbonyl (tert-butyl carbamate; BOC),9-fluorenylmethyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethylcarbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine,trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allylcarbamate. In another embodiment, the protected amino group can be aphthalimide-protected amino group (NPhth).

As used herein, the term “enzyme replacement therapy” or “ERT” refers toadministering an exogenously-produced natural or recombinant enzyme oranalog thereof to a patient in need thereof. In the case of a lyosomalstorage disease, for example, the patient accumulates harmful levels ofa substrate (i.e., material stored) in lysosomes due to a deficiency ordefect in an enzyme responsible for metabolizing the substrate, or dueto a deficiency in an enzymatic activator required for proper enzymaticfunction. Enzyme replacement therapy is provided to the patient toreduce the levels of (i.e., debulk) accumulated substrate in affectedtissues. Enzyme replacement therapies for treating lysosomal storagediseases are known in the art. In accordance with a combination therapyof the disclosure, a lysosomal enzyme, e.g., P-glucocerebrosidase, canbe used for enzyme replacement therapy to reduce the levels ofcorresponding substrate, e.g., β-glucocerebroside, in a patient having alysosomal storage disease such as Gaucher's disease.

As used herein, the term “substrate reduction therapy” or “SRT” is atherapeutic approach used to treat certain metabolic disorders, e.g.,lysosomal storage disorders, in which substrate, e.g., glycolipid,accumulation is counteracted not by replacing the deficient enzyme butby reducing the substrate level to better balance residual activity ofthe deficient enzyme. See, e.g., Coutinho et al., Int. J. Mol. Sci.17:1065 (2016). Substrate reduction therapy and enzyme replacementtherapy (see above) can have unique, independent, and potentiallycomplementary mechanisms of action in the treatment of lyosomal storagedisease and other diseases.

The general principle of SRT is that a substrate reduction agent isadministered to a patient to partially inhibit the biosynthesis of thesubstrate, which accumulates in the absence of a specific lysosomalenzyme. As used herein, the term “substrate reduction agent” is a smallmolecule that reduces the number of substrate molecules requiringcatabolism within the lysosome, thus contributing to balance the rate ofsynthesis with the impaired rate of catabolism. Substrate reductionagents are known in the art.

As used herein, an “effective amount” of an enzyme, when administered toa subject in a combination therapy of the disclosure, is an amountsufficient to improve the clinical course of a lysosomal storagedisease, where clinical improvement is measured by any of the variety ofdefined parameters well known to the skilled artisan.

As used herein the term “small molecule chaperone” refers to a compound,other than a Compound of the Disclosure, that is capable of bindingallosterically or competitively to a mutated enzyme, e.g.,β-galactosidase, thereby stabilizing the enzyme against degradation. Insome embodiments, the small molecule chaperone facilitates properfolding and transport of an enzyme to its site of action. Small moleculechaperones for the treatment of lysosomal storage diseases are known inthe art. See, e.g., US 2016/0207933 A1 and WO 2011/049737 A1.

Synthesis of Compounds of the Disclosure

Another aspect of the disclosure refers to procedures to obtaincompounds of formula (I). The following methods describe the proceduresfor obtaining compounds of general formula (I), or solvates or saltsthereof.

Various synthetic routes for synthesizing compounds of formula (I) aresummarized in the schemes below.

Scheme 1 illustrates the synthetic path to obtain compounds of formula(I) wherein A¹=A²=A³=N. These compounds have formula (Ia).

Scheme 2 illustrates the synthetic path to obtain compounds of formula(I). These compounds have formula (Ib).

Scheme 3 and 4 illustrates the synthetic path to obtain compounds offormula (I) wherein A¹, A² and A³ can be nitrogen atoms in differentcombinations. These compounds have formula (Ib).

Scheme 5 illustrates the synthetic path to obtain compounds of formula(I). These compounds have formula (Ic).

Scheme 6 illustrates the synthetic path to obtain compounds of formula(I). These compounds have formula (Id).

Scheme 7 illustrates the synthetic path to obtain compounds of formula(I) wherein only one of A¹, A² and A³ can be nitrogen atoms. Thesecompounds have formula (Ie).

R¹, R², R³, and n are as defined above for formula (I).

Method 1 Step 1 (Reaction A)

In a first method, according to the disclosure, a compound of formula(II) wherein R³ as defined above is reacted with a dicyandiamide (III)to yield a biguanidine compound of formula (IV) as illustrated inreaction A of the scheme above (Scheme 1).

Reaction A is used to prepare compounds of formula (IV) by reaction ofcompound of formula (II) with a compound of formula (III). Said reactioncan be performed under standard conditions in the presence of a suitableacid or base (e.g., copper sulfate, sodium carbonate, ammonia,methanolic sodium methoxide, hydrogen chloride, hydrogen sulfide ormixtures thereof) and an appropriate solvent (e.g., butanol, water,tetrahydrofuran, xylene, acetone, methanol, ethanol, acetonitrile,2-propanol, dichloromethane dimethylformamide, dimethylsulfoxide ormixture thereof) and, for example, at around room temperature, refluxtemperature or microwave irradiation reaction conditions.

The reaction can also be carried out in the presence of an appropriatecatalyst (or salt thereof) such as iron (III) chloride or copper (II)chloride and also optionally in the presence of an additive orprotecting groups such as chlorotrimethylsilane or trimethylsilyltrifluoromethanesulfonate.

The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after the reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

Step 2 (Reaction B)

The biguanidine (hydrochloride salt or not) compound of formula (IV) issubsequently reacted with a compound of formula (V), wherein X can be—NR¹R², —OPG, —CN, —CHO or —CO₂R⁴, where PG is a protecting group andeach of R¹ and R² is defined above and R⁴ can be methyl or ethyl, toyield a compound of formula (X) as illustrated in reaction B of thescheme above (Scheme 1).

Reaction B is carried out under standard condensation conditions, forexample in the presence of a suitable base (e.g., sodium hydride, sodiummethoxide, sodium ethoxide, sodium tert-butoxide,1,8-diazabicyclo(5.4.0)undec-7-ene or potassium carbonate) and anappropriate solvent (e.g., ethanol, methanol, dimethylformamide ormixture thereof) and for example at around room temperature or refluxtemperature.

The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after the reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

R¹, R², R³, and n are as defined above for formula (I).

Method 2 Step 1 (Reaction C)

In a third method, according to the disclosure, a compound of formula(VI), wherein X can be —NR¹R², —OPG, —CN, —CHO or —CO₂Me, where PG is aprotecting group and each of R¹ and R² is defined above and n is asdefined above, is reacted with a guanidine source, preferably guanidinehydrochloride, to yield a compound of formula (VII) according to thedisclosure as illustrated in reaction C of the scheme above (Scheme 2).

Reaction C is carried out under standard condensation conditions in asuitable solvent and in the presence of a suitable base, such as thoseexplained for step 2 of method 1 described above (Scheme 1).

The compound of formula (VI) is commercially available or can beobtained by procedures described in the literature as is known by theperson skilled in the art.

The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after the reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

Step 2 (Reaction D)

The compound of formula (VII) is subsequently reacted with a compound offormula (II) wherein R³ is as defined above to yield a compound offormula (XI) as illustrated in reaction D of the scheme above (Scheme2).

Reaction D is carried out under standard coupling conditions, in thepresence of a suitable coupling agent (e.g.,(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) andan appropriate base (e.g., N,N-diisopropylethylamine, dimethylaniline,diethylaniline, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, ortriethylamine) in a suitable solvent, such as 1,4-dioxane,tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile, ormixtures thereof.

The reaction mixture is stirred at low temperature, room temperature, orheated until the starting materials have been consumed. The reaction canbe carried out with protecting groups present and those protectinggroups can be removed after the reaction. Suitable protecting groups areknown to the person skilled in the art (see T. W. Greene, “ProtectiveGroups in Organic Synthesis”, 3rd Edition, New York, 1999).

Alternatively, the hydroxyl group of the compound of formula (VII) canbe transformed into a leaving group, such as a halogen, triflate,tosylate, or mesylate group. Said chlorination reaction can be performedunder standard conditions in the presence of a suitable chloride source(e.g., N-chlorosuccinimide, phosphoryl chloride, phosphorouspentachloride or sulfonyl chloride), optionally in the presence of asuitable phase transfer catalyst (e.g., benzyltriethylammonium chlorideor tetramethylammonium chloride) or of a suitable base (e.g.triethylamine, pyridine, N,N-diisopropylethylamine, ammonia, ammoniumchloride or 4-dimethylaminopyridine) and an appropriate solvent (e.g.,acetonitrile, dichloromethane, dimethyl sulfoxide, dimethylformamide,chloroform, N,N-dimethylacetamide, carbon tetrachloride or mixturethereof), and for example, at around room temperature and refluxtemperature.

Alternatively, the hydroxyl group of compound of formula (VII) can betransformed into a triflate, tosylate or mesylate group by reaction ofcompound of formula (VII) with trifluoromethanesulphonic anhydride inthe presence of a suitable base (e.g., pyridine) or p-toluenesulfonylchloride/methanesulfonyl chloride in a suitable solvent (e.g.,dichloromethane) in the presence of an appropriate base (e.g.,triethylamine or pyridine), respectively.

The reaction mixture can be stirred at room temperature or heated untilthe starting materials have been consumed. The reaction can be carriedout with protecting groups present and those protecting groups can beremoved after the reaction. Suitable protecting groups are known to theperson skilled in the art (see T. W. Greene, “Protective Groups inOrganic Synthesis”, 3rd Edition, New York, 1999).

The leaving group is subsequently substituted by reaction with amine(II) to form the corresponding amine group to yield the compound offormula (Ib). The reaction is carried out under standard nucleophilicsubstitution conditions, for example in the presence of a suitable base(e.g., triethylamine, dimethylaniline, diethylaniline pyridine,potassium carbonate or N,N-diisopropylethylamine) or acid (e.g.,sulfuric acid, hydrogen chloride or acetic acid) or absence of base oracid, optionally in the presence of a suitable catalyst, ligand and base(e.g., Pd(dba)₂, XantPhos and cesium carbonate) and an appropriatesolvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide,propanol, N-methylpyrrolidine, 1-methylpiperizine, dioxane, ethanol,methanol, butanol, dimethylformamide, dimethylsulphoxide,tetrahydrofuran, acetonitrile, toluene or mixture thereof).

The reaction mixture is stirred at low temperature, room temperature,reflux temperature, or microwave irradiation reaction conditions. Thereaction can be carried out with protecting groups present and thoseprotecting groups can be removed after reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

R¹, R², R³, and n are as defined above for formula (I).

Method 3 (Reaction E)

In another method, according to the disclosure, a compound of formula(XII), wherein A¹, A², A³, R³ and n are as defined above and X can bedifferent amine precursors, such as —OPG, —CHO, —CN or —CO₂R⁴, where PGis a protecting group, is reacted with an amine (VIII), wherein R¹ andR² are as defined above, to yield a compound of formula (Ib) accordingto the disclosure as illustrated in reaction E of the scheme above(Scheme 3).

When X=—OPG and —CHO

The alcohol compound of formula (XII) is deprotected by standard methodsand subsequently transformed in the corresponding aldehyde understandard oxidation conditions, for example, in the presence of asuitable oxidative agent (e.g., oxalyl chloride, manganese oxide orsulfur trioxide pyridine complex) and an appropriate base, such astriethylamine in a suitable solvent (e.g., dichloromethane,tetrahydrofuran, dimethylsulfoxide or mixtures thereof). The reactionmixture can be stirred at room temperature or heated until the startingmaterials have been consumed.

The aldehyde of the compound of formula (Ib) is subsequently convertedby reaction with the amine (VIII) to a corresponding amine group toyield the compound of formula (Ib) according to the disclosure asillustrated in reaction E of the scheme above (Scheme 3). Thistransformation is carried out under standard condensation conditions,for example, in the presence of an appropriate reducing agent (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride), alternativelyin the presence of a suitable acid, such as acetic acid and appropriatesolvent (e.g., dichloromethane, dichloroethane, methanol, toluene ormixture thereof).

The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after the reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

When X=-LG

The X group of the compound of formula (XII) is converted into a leavinggroup by standard methods, for instance the hydroxyl group of compoundof formula (XII) can be transformed into a leaving group such ashalogen, triflate, tosylate or a mesylate group.

The leaving group of the compound of formula (XII) is converted byreaction with an amine (VIII) to a corresponding amine group to yieldthe compound of formula (Ib) according to the disclosure as illustratedin reaction E of the scheme above (Scheme 3). Reaction E is carried outunder standard nucleophilic substitution conditions, for example in thepresence a suitable base (e.g., N,N-diisopropylethylamine,4-dimethylaminopyridine, 2,6-lutidine, triethylamine, pyridine, ammoniumchloride, sodium hydride, potassium carbonate, sodium carbonate, sodiumhydrogen carbonate, sodium hydroxide, sodium acetate or sodium nitrite)and an appropriate solvent (e.g., acetonitrile, dichloromethane,tetrahydrofuran, benzene, diethyl ether, toluene, dimethylformamide,water, ethanol or mixture thereof). Such reactions can be used a base oracid in a further step such as, acetic acid, hydrogen chloride or sodiumhydroxide.

The reaction mixture is stirred at a low temperature or roomtemperature, or heated until the starting materials have been consumed.The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

When X=—CN

The cyano group of the compound of formula (XII) is subsequently reducedin the appropriate aldehyde group under standard reductive conditions inthe presence of a suitable reducing agent or catalyst (e.g.,diisobutylaluminum hydride, sodium hypophosphite, lithium aluminumhydride, nickel, aluminum oxide, platinum oxide), an appropriate solvent(e.g., dichloromethane, tetrahydrofuran, ether, methanol, ethanol, wateror mixture thereof) and for example, at around −78° C., roomtemperature, reflux or microwave irradiation reaction conditions. Thereaction can also be carried out in the presence of an acid, such asacetic acid or base (e.g., pyridine) or under hydrogen atmosphere.

The aldehyde group can be subsequently converted to the correspondingamine under standard conditions, such as those explained for Method 3,when X is CHO.

The cyano compound can be prepared by reaction of the compound whenX=-LG with a cyanide source. Said reaction can be performed understandard cyanation conditions in the presence of a suitable cyanidesource (e.g., zinc cyanide) under the catalysis of a suitable catalyst,such as tetrakis(triphenylphosphine) palladium(0), in a suitable solvent(e.g., tetrahydrofuran, toluene, dimethylformamide, N-methylpyrrolidoneor mixture thereof) at around room temperature or reflux temperature.

When X=—CO₂R⁴

The ester of the compound of formula (XII) is subsequently converted toa substituted amide group to yield the compound of formula (Ib)according to the disclosure as illustrated in reaction E of the schemeabove (Scheme 3).

Reaction E is carried out under standard amidation conditions, forexample in the presence of a suitable metal or base catalyst (e.g.,trimethylaluminum, antimony(III) ethoxide, indium(III) iodide,titanium(IV) isopropoxide, zirconium(IV) tert-butoxide, hafnium(IV)tert-butoxide, zinc dust, sodium methoxide, potassium methoxide,1,8-Diazabicyclo[5.4.0]undec-7-ene,1,3-bis(2,4,6-trimethylphenyl)-imidazolium, (PNN)Ru(II),Di-p-chloro-bis[chloro-(pentamethylcyclopentadienyl)-iridium(III)],lanthanum(III) trifluoromethane-sulfonate, or magnesium nitride),optionally in the presence of a suitable additive (e.g.,1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, hydroxyproline, or4-trifluoromethylphenol) and an appropriate solvent (e.g., methanol,tetrahydrofuran, acetonitrile, 2-methyltetrahydrofuran, toluene,benzene, dichloromethane, water, chloroform dimethylformamide, ormixtures thereof) or absence of solvent. Such reactions can be performedin the presence of a further base, such as potassium tert-butoxide orsodium acetate.

This reaction can be carried out under microwave irradiation reactionconditions.

Alternatively, the ester group can be hydrolyzed to the carboxylic acidgroup following standard methods and then the acid can be converted tothe amide under standard condensation or amide coupling conditions, forexample in the presence of a suitable coupling agent (e.g.,1,1′-carbonyldiimidazole, N,N′-cyclohexylcarbodiimide,1-β-dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloride thereof),N,N′-disuccinimidyl carbonate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(i.e. O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), benzotriazol-1-yloxytris-pyrrolidinophosphoniumhexafluorophosphate, bromo-tris-pyrrolidinophosphoniumhexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetra-fluorocarbonate, 1-cyclohexylcarbodiimide-3-propyloxymethylpolystyrene, 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexfluoroborate), optionally in the presence of a suitable base (e.g.,sodium hydride, sodium bicarbonate, potassium carbonate, pyridine,triethylamine, dimethylaminopyridine, diisopropylamine, sodiumhydroxide, potassium tert-butoxide, and/or lithium diisopropylamide (orvariants thereof)) and an appropriate solvent (e.g., tetrahydrofuran,pyridine, toluene, dichloromethane, chloroform, acetonitrile,dimethylformamide, trifluoromethylbenzene, dioxane, or triethylamine).Such reactions can be performed in the presence of a further additive,such as 1-hydroxybenzotriazole hydrate.

The reaction mixture is stirred at a low temperature or roomtemperature, or heated until the starting materials have been consumed.The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3rd Edition, New York, 1999).

Subsequently, the amide group is reduced to the corresponding amine inthe presence of a suitable reducing agent (e.g., aluminum hydride orborane) and an appropriate solvent, such as tetrahydrofuran,dichloromethane, dioxane, toluene or a mixture thereof, at around roomtemperature or reflux temperature. Every reaction can be carried outwith protecting groups present and those protecting groups can beremoved after the reaction. Suitable protecting groups are known to theperson skilled in the art (see T. W. Greene, “Protective Groups inOrganic Synthesis,” 3rd Edition, New York, 1999).

R¹, R², R³, and n are as defined above.

Method 4 Step 1 (Reaction F)

In another method, according to the disclosure, in a compound of formula(XIII), wherein A¹, A², A³ and n are defined above and X can bedifferent amine precursors, such as —OPG, —CHO, —CN or —CO₂R⁴, where PGis a protecting group, the group X can be transformed into the —NR¹R²group before the final amine —NHR³ to yield (Ib) according to thedisclosure as illustrated in reaction F of the scheme above (Scheme 4)following standard conditions like the ones described in reaction E ofScheme 3.

The reaction can be carried out with protecting groups present, forinstance on the —NH₂ moiety, and those protecting groups can be removedafter reaction. Suitable protecting groups are known to the personskilled in the art, for instance 2,4,4-trimethylpentan (see T. W.Greene, “Protective Groups in Organic Synthesis,” 3rd Edition, New York,1999).

Step 2 (Reaction G)

Compound of formula (XIV) is subsequently reacted with compound offormula (II), wherein R³ is defined above to yield a compound of formula(I) as illustrated in reaction G of the scheme above (Scheme 4).

Reaction G is carried out under standard nucleophilic substitutionconditions in a suitable solvent and in the presence of a suitable base,such as those explained for reaction D (Scheme 2).

R¹, R², R³, and n are as defined above.

Method 5 Step 1 (Reaction H)

In another method, according to the disclosure, a compound of formula(IX), wherein X can be —NR¹R², —OPG, —CN, —CHO or —CO₂Me, where PG is aprotecting group and each of R¹ and R² and n is as defined above, isreacted with diethyl malonate to yield a compound of formula (XV) asillustrated in reaction H of the scheme above (Scheme 5).

Reaction H is carried out under standard condensation conditions in asuitable solvent and in the presence of a suitable base, such as thoseexplained for step 2 of method 1 described above (Scheme 1).

Compounds of formula (IX) are commercially available or can be obtainedby procedures described in the literature as is known by the personskilled in the art.

Step 2 (Reaction I)

Subsequently, the hydroxyl groups of the compound of formula (XV) aretransformed to chlorides to yield a compound of formula (XVI) accordingto the disclosure as illustrated in reaction I of the Scheme 5 above.

Reaction I is carried out under standard chlorinated conditions, in thepresence of appropriate chlorinated agents, such as phosphoryl chloride,phosphorus pentachloride, cobalt chloride or bis(trichloromethyl)carbonate, and a suitable base (e.g., triethylamine, N,N-diethylaniline,N,N-diisopropylethylamine or 4-(dimethylamino)pyridine) and anappropriate solvent, such as dimethylformamide, dichloromethane,tetrahydrofuran or mixture thereof.

The reaction mixture is stirred at a low temperature, room temperature,or heated until the starting materials have been consumed. The reactioncan be carried out with protecting groups present and those protectinggroups can be removed after reaction. Suitable protecting groups areknown to the person skilled in the art (see T. W. Greene, “ProtectiveGroups in Organic Synthesis,” 3rd Edition, New York, 1999).

Step 3 (Reaction J)

One of the chlorides of the compound of formula (XVI) is subsequentlysubstituted by reaction with an amine (II) to form the correspondingamino group to yield the compound of formula (XVII) according to thedisclosure as illustrated in reaction J of the scheme above (Scheme 5).

Reaction J is carried out under standard nucleophilic substitutionconditions, for example in the presence of a suitable base (e.g.,triethylamine, pyridine, potassium carbonate orN,N-diisopropylethylamine) or acid (e.g., sulfuric acid, hydrogenchloride or acetic acid) or absence of base or acid, optionally in thepresence of a suitable catalyst, ligand and base (e.g., Pd(dba)₂,XantPhos and cesium carbonate) and an appropriate solvent (e.g.,ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol,N-methylpyrrolidine, 1-methylpiperizine, dioxane, butanol, or a mixturethereof).

The reaction mixture is stirred at a low temperature, room temperature,or heated until the starting materials have been consumed. The reactioncan be carried out with protecting groups present and those protectinggroups can be removed after reaction. Suitable protecting groups areknown to the person skilled in the art (see T. W. Greene, “ProtectiveGroups in Organic Synthesis,” 3^(rd) Edition, New York, 1999).

Step 4 (Reaction K)

The remaining chloride of the compound of formula (XVII) is subsequentlysubstituted by reaction with an amine to form the corresponding aminogroup to yield the compound of formula (XVIII) according to thedisclosure as illustrated in reaction K of the scheme above (Scheme 5).Reaction K is used to prepare compounds of formula (XVIII) by reactionof compound of formula (XVII) with the appropriate amine. Said reactioncan be performed under standard conditions in the presence of a suitablepalladium catalyst, such as Pd(dba)₂, palladium acetate or Pd₂(dba)₃,the appropriate base (cesium carbonate or triethylamine, among others)and a suitable ligand, such as1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene, Xantphos orXPhos, in the appropriate solvent (e.g., butanol, toluene, dioxane ormixture thereof) and, for example, at around room temperature or refluxtemperature.

Alternatively, the transformation can be carried out in the presence ofa suitable base (e.g., N,N-Diisopropylethylamine or triethylamine) andan appropriate solvent, such as dimethyl sulphoxide, tetrahydrofuran,dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol, ora mixture thereof.

The reaction can be carried out with protecting groups present and thoseprotecting groups can be removed after reaction. Suitable protectinggroups are known to the person skilled in the art (see T. W. Greene,“Protective Groups in Organic Synthesis,” 3^(rd) Edition, New York,1999).

R¹, R², R³, and n are as defined above.

Method 6 Step 1 (Reaction L)

In another method, according to the disclosure, a compound of formula(XIX), wherein X can be —NR¹R², —OPG, —CN, —CHO or —CO₂Me, where PG is aprotecting group and each of R¹ and R² and n are as defined above, isreacted with an amine source (for instance NH₂BOC) to yield a compoundof formula (XX) as illustrated in reaction L of the scheme above (Scheme6).

Reaction L is carried out under standard aromatic nucleophilicsubstitution conditions, such as those explained for step 4 of method 5described above (Scheme 5).

Step 2 (Reaction M)

Subsequently, a compound of formula (XX), wherein X can be —NR¹R², —OPG,—CN, —CHO or —CO₂Me, where PG is a protecting group and each of R¹ andR² and n are as defined above, is reacted with an aniline group whereinR³ is defined above to yield a compound of formula (XXI) as illustratedin reaction M of the scheme above (Scheme 6).

Reaction M is carried out under standard aromatic nucleophilicsubstitution conditions, such as those explained for step 3 of method 5described above (Scheme 5).

R¹, R², R³, and n are as defined above.

Method 7 Step 1 (Reaction N)

In another method, according to the disclosure, a pyridine compound offormula (XXII), wherein n is as defined above and only one of A¹, A² orA³ is N, is reacted with an aniline group of formula (VIII), whereineach of R¹ and R² are as defined above, to yield a compound of formula(XXIII) as illustrated in reaction N of the scheme above (Scheme 7).

Reaction N is carried out under conditions, such as those explained formethod 3 when X is —CO₂R⁴ described above (Scheme 3).

Step 2 (Reaction O)

The compound of formula (XXIII) is reacted with an aniline group (II),wherein R³ is as defined above, to yield a compound of formula (XXIV)according to the disclosure as illustrated in reaction O of the schemeabove (Scheme 7).

Reaction O is carried out under standard amine arylation conditions,such as those explained for step 3 of a method 5 described above (Scheme5).

Step 3 (Reaction P)

The compound of formula (XXIV) is reacted with an amine source (forinstance a NH₂BOC) to yield a compound of formula (Ie) according to thedisclosure as illustrated in reaction P of the scheme above (Scheme 7).

Reaction P is carried out under standard amine arylation conditions,such as those explained for step 4 of a method 5 described above (Scheme5).

Use of the Compounds of the Disclosure

Compounds of the Disclosure have the ability to increaseβ-glucocerebrosidase. Therefore, Compounds of the Disclosure can beused/administered to treat and/or prevent lysosomal storage diseases. Inone embodiment, the lysosomal storage disease is Gaucher's disease.

Accordingly, the present disclosure is directed to a method of treatingor preventing a lysosomal storage disease, comprising administering to apatient in need thereof an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present disclosure is directed to a method oftreating or preventing Gaucher's disease, comprising administering to apatient in need thereof an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the method of treating or preventing a lysosomalstorage disease, such as Gaucher's disease, further comprisesadministering to the patient at least one other therapeutic agent. Inanother embodiment, the therapeutic agent is an effective amount of anenzyme for enzyme replacement therapy. In another embodiment, the enzymeis β-glucocerebrosidase or an analog thereof. In another embodiment, theenzyme is imiglucerase. In another embodiment, the therapeutic agent isan effective amount of a small molecule chaperone. In anotherembodiment, the small molecule chaperone binds competitively to anenzyme. In another embodiment, the small molecule chaperone is selectedfrom the group consisting of iminoalditols, iminosugars, aminosugars,thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase,phosphatase, and peptidase inhibitors. In another embodiment, the smallmolecule chaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), andambroxol. In another embodiment, the small molecule chaperone ismiglustat. In another embodiment, the therapeutic agent is an effectiveamount of substrate reduction agent for substrate reduction therapy. Inanother embodiment, the substrate reduction agent is miglustat.

The disclosure provides the following particular embodiments relating tomethods of treating or preventing a disease, condition, or disorder in apatient designated as [I] for the first embodiment, [II] for the secondembodiment, and so on.

-   [I]. A method of treating or preventing a disease, disorder, or    condition in a patient, comprising administering to a patient in    need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independent selected from the group consisting of halogen,—C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN;

n is 1 or 2, wherein the alkylene chain can be optionally substitutedwith one or more —C₁₋₄ alkyl groups;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and

R² is selected from the group consisting of hydrogen, —C₁₋₄ alkyl, and—C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl is optionally substitutedwith —O(C₁₋₄)alkyl optionally substituted with —O(C₁₋₄)NH₂, hydroxy,—CN, halogen, or —N(Rb)₂; or R¹ and R² together with the nitrogen atomto which they are attached form an optionally substituted 5- to10-membered heterocyclic ring, wherein said heterocyclic ring optionallycontains 1, 2, or 3 additional heteroatoms selected from the groupconsisting of N, S, or O, and wherein said heterocyclic ring isoptionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,and —C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein saidalkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkylor heterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and

R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.

-   [II]. The method of [I], wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

with the proviso that no more than two of A¹, A², or A³ is N;

each R⁴ is independently selected from the group consisting of halogen,—C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or —C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,and —C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein saidalkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkylor heterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

-   [III]. The method of [I] or [II], wherein A¹ is N and A² and A³ are    each independently selected from the group consisting of CH and    C(R⁴).-   [IV]. The method of [I] or [II], wherein A² is N and A¹ and A³ are    each independently selected from the group consisting of CH and    C(R⁴).-   [V]. The method of [I] or [II], wherein A³ is N and A¹ and A² are    each independently selected from the group consisting of CH and    C(R⁴).-   [VI]. The method of [I] or [II], wherein A¹ and A² are both N and A³    is CH or C(R⁴).-   [VII]. The method of [I] or [II], wherein A¹ and A³ are both N and    A² is CH or C(R⁴).-   [VIII]. The method of [I] or [II], wherein A² and A³ are both N and    A¹ is CH or C(R⁴).-   [IX]. The method of any one of [I]-[VIII], wherein n is 1.-   [X]. The method of any one of [I]-[VIII], wherein n is 2.-   [XI]. The method of any one of [I]-[X], or a pharmaceutically    acceptable salt or solvate thereof, wherein R³ is unsubstituted    —C₆₋₁₀ aryl or —C₆₋₁₀ aryl substituted with 1 or 2 substituents each    independently selected from the group consisting of halogen,    hydroxy, —CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂,    —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyl optionally substituted with 1, 2,    or 3 substituents each independently selected from the group    consisting of halogen, —CN, —O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and    —NH(C₁₋₄ alkyl).-   [XII]. The method of any one of [I]-[XI], wherein R² is H.-   [XIII]. The method of any one of [I]-[XI], wherein R² is —C₁₋₄    alkyl.-   [XIV]. The method of any one of [I]-[XI] or [XIII], wherein R² is    methyl.-   [XV]. The method of any one of [I]-[XIV], wherein R¹ is —C₆₋₁₀ aryl    or —C₁₋₄ alkyl-C₆₋₁₀ aryl, wherein said aryl or alkylaryl is    optionally substituted with 1, 2 or 3 groups each independently    selected from the group consisting of halogen, hydroxy, —CN, —ORb,    —SRb, —N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3    halogen atoms, optionally substituted —C₆₋₁₀ aryl, optionally    substituted -(5- to 10-membered)-C₁₋₉ heteroaryl, and -(5- to    10-membered)-C₂₋₉ heterocyclyl, wherein Rb is as defined in [I].-   [XVI]. The method of any one of [I]-[XV], wherein Rb is hydrogen or    —C₁₋₄ alkyl.-   [XVII]. The method of any one of [I]-[XI], wherein R¹ and R²    together with the nitrogen atom to which they are attached form an    optionally substituted 5- to 10-membered heterocyclic ring, wherein    said heterocyclic ring optionally contains 1, 2, or 3 additional    heteroatoms selected from the group consisting of N, S, or O, and    wherein said heterocyclic ring is optionally fused to a phenyl ring.-   [XVIII]. The method of [XVII], wherein R¹ and R² together with the    nitrogen atom to which they are attached form a 5- or 6-membered    ring optionally fused to a phenyl ring.-   [XIX]. The method of [I], wherein the compound of formula (I) is    selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XX]. The method of [I], wherein the compound of formula (I) is    selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XXI]. A method of treating or preventing a disease, disorder, or    condition in a patient, comprising administering to a patient in    need thereof an effective amount of a compound selected from the    group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XXII]. A method of treating or preventing a disease, disorder, or    condition in a patient, comprising administering to a patient in    need thereof an effective amount of a compound selected from the    group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XXIII]. The method of [I], wherein A¹, A² and A³ are N.-   [XXIV]. The method of [XXIII], wherein the compound administered is    selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XXV]. The method of [XXIII], wherein the compound administered is    selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

-   [XXVI]. The method of any one of [I]-[XXV], further comprising    administering to the patient at least one other therapeutic agent.-   [XXVII]. The method of [XXVI], wherein the therapeutic agent is an    effective amount of an enzyme for enzyme replacement therapy.-   [XXVIII]. The method of [XXVII], wherein the enzyme is    β-glucocerebrosidase or an analog thereof.-   [XXIX]. The method of [XXVIII], wherein the enzyme is imiglucerase.-   [XXX]. The method of any one of [XXVI]-[XXIX], wherein the    therapeutic agent is an effective amount of a small molecule    chaperone.-   [XXXI]. The method of [XXX], wherein the small molecule chaperone    binds competitively to an enzyme.-   [XXXII]. The method of [XXX] or [XXXI], wherein the small molecule    chaperone is selected from the group consisting of iminoalditols,    iminosugars, aminosugars, thiophenylglycosides, glycosidase,    sulfatase, glycosyl transferase, phosphatase, and peptidase    inhibitors.-   [XXXIII]. The method of [XXXII], wherein the small molecule    chaperone is selected from the group consisting of isofagomine,    N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat.-   [XXXIV]. The method of any one of [XXVI]-[XXXIII], wherein the    therapeutic agent is an effective amount of a substrate reduction    agent for substrate reduction therapy.-   [XXXV]. The method of [XXXIV], wherein the substrate reduction agent    is miglustat.-   [XXXVI]. The method of any one of [I]-[XXXV], wherein the disease,    disorder, or condition is a lysosomal storage disease.-   [XXXVII]. The method of [XXXVI], wherein the lysosomal storage    disease is Gaucher's disease.-   [XXXVIII]. The method of any one of [I]-[XXXV], wherein the disease,    disorder, or condition is Parkinson's disease, Lewy body disease,    dementia, multiple system atrophy, epilepsy, bipolar disorder,    schizophrenia, an anxiety disorder, major depression, polycyctic    kidney disease, type 2 diabetes, open angle glaucoma, multiple    sclerosis, or multiple myeloma.

The present disclosure is also directed to a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use in thetreatment of prevention of a lysosomal storage disease, such asGaucher's disease, in a patient in need of such treatment or prevention.

The present disclosure is also directed to the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for treating and/or preventing alysosomal storage disease, such as Gaucher's disease, in a patient inneed of such treatment or prevention.

The present disclosure is also directed to a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use intreating or preventing a lysosomal storage disease, such as Gaucher'sdisease, in a patient. In one embodiment, the compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, isadministered to the patient in combination with at least one othertherapeutic agent. In another embodiment, the therapeutic agent is aneffective amount of an enzyme for enzyme replacement therapy. In anotherembodiment, the enzyme is β-glucocerebrosidase or an analog thereof. Inanother embodiment, the enzyme is imiglucerase. In another embodiment,the therapeutic agent is an effective amount of a small moleculechaperone. In another embodiment, the small molecule chaperone bindscompetitively to an enzyme. In another embodiment, the small moleculechaperone is selected from the group consisting of iminoalditols,iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase,glycosyl transferase, phosphatase, and peptidase inhibitors. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat. In another embodiment, the small moleculechaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In anotherembodiment, the small molecule chaperone is miglustat.

The present disclosure is also directed to a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use in thetreatment or prevention of a lysosomal storage disease, such asGaucher's disease, in a patient in need of such treatment or prevention.

The present disclosure is also directed to the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for treating and/or preventing alysosomal storage disease, such as Gaucher's disease, in a patient inneed of such treatment or prevention.

Synucleinopathies are neurodegenerative diseases characterized by theabnormal accumulation of aggregates of α-synuclein protein in neurons,nerve fibres, or glial cells. There is a well-established clinicalassociation between mutations in the glucocerebrosidase gene and thedevelopment of more prevalent multifactorial disorders includingParkinson's disease and other synucleinopathies. See, Siebert, M., etal., Brain 137:1304-1322 (2014). According to Siebert et al., there is areciprocal relationship between glucocerebrosidase activity (wild-typeand mutant) and α-synuclein in synucleinopathiesm such as Parkinson;sdisease and dementia with Lewy bodies. This reciprocal relationshipsuggests that therapies for Gaucher's disease, which are targetedtowards augmenting glucocerebrosidase activity or decreasingglucocerebrosides storage could prove to be provising strategies formodulating α-synuclein proteostasis and its subsequent aggregation andoligomerization.

Compounds of the Disclosure, based on their activities as describedherein, can be used/administered to treat and/or preventsynucleinopathies, such as Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycyctic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis, andmultiple myeloma.

Accordingly, the present disclosure is also directed to a method oftreating or preventing a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma,comprising administering to a patient in need thereof an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof. In another embodiment, Parkinson's disease istreated or prevented. In another embodiment, the method furthercomprises administering to the patient at least one other therapeuticagent. In another embodiment, the therapeutic agent is an effectiveamount of an enzyme for enzyme replacement therapy. In anotherembodiment, the enzyme is β-glucocerebrosidase or an analog thereof. Inanother embodiment, the enzyme is imiglucerase. In another embodiment,the therapeutic agent is an effective amount of a small moleculechaperone. In another embodiment, the small molecule chaperone bindscompetitively to an enzyme. In another embodiment, the small moleculechaperone is selected from the group consisting of iminoalditols,iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase,glycosyl transferase, phosphatase, and peptidase inhibitors. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat. In another embodiment, the small moleculechaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In anotherembodiment, the small molecule chaperone is miglustat.

The present disclosure is also directed to a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use intreating or preventing a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma, in apatient. In one embodiment, the compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, is administered tothe patient in combination with at least one other therapeutic agent. Inanother embodiment, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is for use in treating or preventingParkinson's disease. In another embodiment, the therapeutic agent is aneffective amount of an enzyme for enzyme replacement therapy. In anotherembodiment, the enzyme is β-glucocerebrosidase or an analog thereof. Inanother embodiment, the enzyme is imiglucerase. In another embodiment,the therapeutic agent is an effective amount of a small moleculechaperone. In another embodiment, the small molecule chaperone bindscompetitively to an enzyme. In another embodiment, the small moleculechaperone is selected from the group consisting of iminoalditols,iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase,glycosyl transferase, phosphatase, and peptidase inhibitors. In anotherembodiment, the small molecule chaperone is selected from the groupconsisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat. In another embodiment, the small moleculechaperone is selected from the group consisting of isofagomine,N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In anotherembodiment, the small molecule chaperone is miglustat.

The present disclosure is also directed to a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use in thetreatment or prevention of a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma in apatient in need of such treatment or prevention.

The present disclosure is also directed to the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for treating and/or preventing adisease or disorder selected from the group consisting of Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycyctic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, and multiple myeloma in a patient in need of suchtreatment or prevention.

Pharmaceutical Compositions

The present disclosure is also directed to pharmaceutical compositions,comprising an effective amount of a Compound of the Disclosure, or apharmaceutically acceptable salt or solvate thereof, and at least onepharmaceutically acceptable excipient.

Due to their activity, Compounds of the Disclosure can be used in humanmedicine. As described above, Compounds of the Disclosure are useful fortreating or preventing Gaucher's disease. Compounds of the Disclosurecan be administered to any patient suffering said condition. The term“patient” as used herein refers to any human that can experience thebeneficial effects of a Compound of the Disclosure.

When administered to a patient, a Compound of the Disclosure can beadministered as a component of a composition that comprises apharmaceutically acceptable excipient or carrier.

The Compound of the Disclosure can be administered in combination withat least one other therapeutic agent. Administration of the Compound ofthe Disclosure with at least one other therapeutic agent can besequential or concurrent. In one embodiment, the Compound of theInvention and the at least one other therapeutic agent are administeredin separate dosage forms. In another embodiment, the Compound of theInvention and the at least one other therapeutic agent are administeredconcurrently in the same dosage form.

The term “excipient” refers to a vehicle, diluent, or adjuvant that isadministered with the active ingredient. Such pharmaceutical excipientscan be sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable, or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil, and similar. Water or salineaqueous solutions and aqueous dextrose and glycerol solutions, forexample, for injectable solutions, can be used as vehicles. Suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by E. W. Martin, 21^(st) Edition, 2005; or “Handbook ofPharmaceutical Excipients,” Rowe C. R.; Paul J. S.; Marian E. Q., sixthEdition, incorporated herein by reference.

Examples of pharmaceutical compositions include any solid composition(tablets, pills, capsules, granules, etc.) or liquid compositions(solutions, suspensions, or emulsions) for oral, topical, or parenteraladministration.

In another embodiment, the pharmaceutical compositions are in an oraldelivery form. Pharmaceutical forms suitable for oral administration canbe tablets and capsules, and can contain conventional excipients knownin the art, such as binders, for example syrup, gum Arabic, gelatin,sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for examplelactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycine;lubricants for the preparation of tablets, for example magnesiumstearate; disintegrants, for example starch, polyvinylpyrrolidone,sodium starch glycolate, or microcrystalline cellulose; orpharmaceutically acceptable wetting agents, such as sodium laurylsulphate.

Solid oral compositions can be prepared by conventional methods ofblending, filling, or preparation of tablets. Repeated blendingoperations can be used to distribute the active ingredient in all thecompositions that use large amounts of fillers. Such operations areconventional in the art. The tablets can be prepared, for example, bydry or wet granulation and optionally can be coated by well knownmethods in normal pharmaceutical practice, in particular using entericcoating.

Pharmaceutical compositions can also be adapted for parenteraladministration, such as sterile solutions, suspensions, or lyophilizedproducts in the appropriate unit dosage form. Suitable excipients, suchas fillers, buffering agents, or surfactants can be used.

The mentioned formulations can be prepared using standard methods, suchas those described or referred to in the Spanish and U.S. Pharmacopoeiasand similar reference texts.

In general, the effective amount of a Compound of the Disclosure to beadministered depends on the relative efficacy of the compound chosen,the severity of the condition or disorder being treated, and thepatient's weight. The active compound can be administered one or moretimes a day, for example 1, 2, 3, or 4 times daily, with typical totaldaily doses in the range from about 0.01 mg/kg of body weight/day toabout 1000 mg/kg of body weight/day. In another embodiment, theeffective dosage amount of a Compound of the Disclosure is about 500mg/kg of body weight/day or less. In another embodiment, the effectivedosage amount of a Compound of the Disclosure is about 100 mg/kg of bodyweight/day or less. In another embodiment, the effective dosage amountranges from about 0.01 mg/kg of body weight/day to about 100 mg/kg ofbody weight/day of a Compound of the Disclosure; in another embodiment,from about 0.02 mg/kg of body weight/day to about 50 mg/kg of bodyweight/day of a Compound of the Disclosure; and in another embodiment,from about 0.025 mg/kg of body weight/day to about 20 mg/kg of bodyweight/day of a Compound of the Disclosure.

A composition of the disclosure can be prepared by a method comprisingadmixing a Compound of the Disclosure with a pharmaceutically acceptableexcipient or carrier. Admixing can be accomplished using methods knownfor admixing a compound and a pharmaceutically acceptable excipient orcarrier. In another embodiment, the Compound of the Disclosure ispresent in the composition in an effective amount.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present disclosure. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the disclosure.

General Experimental Conditions

The compound IUPAC names given herein were generated with ChemBioDrawUltra 12.0., 12.0.2., or 16.0.

Hereinafter, the term “h” means hours, “eq” means equivalents, “min”means minutes, “Pd₂(dba)₃” meanstris(dibenzylideneacetone)-dipalladium(0), “Pd(PPh₃)₄” meanspalladium-tetrakis(triphenylphosphine), “DavePhos” means2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; “XPhos” means2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, “Zn(CN)₂” meanszinc(II) cyanide, “HPLC” means high-performance liquid chromatography,“TLC” means thin layer chromatography, “LC-MS” or “HPLC-MS” means Liquidchromatography-mass spectrometry, “CD₃OD” means deuterated methanol,“CDCl₃” means deuterated chloroform, “DMSO-d₆” means deuterated dimethylsulfoxide, “BOC group” means tert-butyloxycarbonyl group, and “HATU”means 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro-phosphate.

¹H NMR spectra were recorded in a Bruker (400 MHz and 500 MHz) and in aVarian Mercury 400 MHz spectrometer (at room temperature).

HPLC spectra were recorded on Waters 2695, Agilent 1260Infibity-2{circumflex over ( )}Waters UPLC-H class.

MW calculated is an isotopic average and the “found mass” is referringto the most abundant isotope detected in the LC-MS.

LC-MS analysis of the compounds was conducted as per one of thefollowing methods.

Method A: X-BRIDGE C18 (4.6 mm×75 mm, 3.5 m); wavelength: 215 nm; flow:2.0 mL/min; run time: 5.0 min; Mobile phase A: 10 mM ammonium acetate inwater and B: 100% acetonitrile; Time and mobile phase-gradient (time inmin/% B): 0.0/10, 0.2/10, 2.5/75, 3.0/100, 4.8/100, 5.0/10; MASS:Agilent 1200 SERIES, Mass: 6130SQD (ESI/APCI).

Method B: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 m); wavelength: 215 nm;flow: 0.8 mL/min; run time: 3.0 min; Mobile phase A: 0.1% of formic acidin water and B: 1.0% formic acid in acetonitrile; Time and mobilephase-gradient (time in min/% B): 0.0/2, 0.2/2, 1.5/98, 2.6/98, 2.61/2,3.2/2; MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI/APCI).

Method C: YMC-Pack ODS-AQ (50 mm×4.6 mm, S-3 μm, 12 mm); wavelength: 215nm; flow: 1.6 mL/min at 50° C.; run time: 3.5 min; mobile phase A: 0.1%of formic acid in water and B: 0.1% formic acid in acetonitrile; Timeand mobile phase-gradient (time in min/% B): 5% B-100% B in 3.5 min;MASS: micromass ZQ4000.

Method D: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 m); wavelength: 215 nm;flow: 0.6 mL/min; run time: 3.2 min; Mobile phase A: 10 mM ammoniumacetate in water and B: 100% acetonitrile; Time and mobilephase-gradient (time in min/% B): 0.0/98, 0.5/98, 8.5/2.9, 2/2, 9.5/98,10/98; MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI/APCI).

Method E: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); wavelength: 215nm; flow: 0.6 mL/min; run time: 3.2 min; Mobile phase A: 0.1% of formicacid in water and B: 0.1% formic acid in acetonitrile; Time and mobilephase-gradient (time in min/% A): 0/97, 0.3/97, 3.0/2, 4.0/2, 4.2/97,4.5/97; MASS: Waters Acquity UPLC with SQD (ESI/APCI).

Method F: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 m); wavelength: 215 nm;flow: 0.8 mL/min; run time: 3.2 min; Mobile phase A: 0.1% of formic acidin water and B: 1.0% formic acid in acetonitrile; Time and mobilephase-gradient (time in min/% A): 0.0/98, 0.5/98, 3.4/2, 4.2/2, 4.5/98,5/98; MASS: Waters Acquity UPLC with SQD (ESI/APCI).

Method G: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); wavelength: 215nm; flow: 0.6 mL/min; run time: 3.2 min; Mobile phase A: 0.1% of formicacid in water and B: Acetonitrile; Time and mobile phase-gradient (timein min/% A): 0.0/98, 0.5/98, 3.4/2, 4.2/2, 4.5/98; MASS: Waters AcquityUPLC with SQD (ESI/APCI).

Method H: X-BRIDGE C18 (2.5 mm×50 mm 1.7 μm); wavelength: 220 nm; flow:0.6 mL/min; run time: 4.0 min; Mobile phase A: 10 mM ammonium acetate inwater and B: 100% acetonitrile; Time and mobile phase-gradient (time inmin/% B): 0.0/5, 0.3/5, 2.0/98, 3.5/98, 3.6/5; MASS: Agilent 1200SERIES, Mass: 6130SQD (ESI/APCI).

Intermediate 1

To a stirred solution of ethyl bromoacetate (1 eq) in dichloromethane(1.25 mL/mmol) at 0° C. were added N-methylbenzylamine (1 eq) anddiisopropylamine (2.4 eq). The reaction mixture was warmed to roomtemperature and stirred for 6 h. After reaction completion, the reactionmixture was poured into saturated sodium bicarbonate solution and theorganic product was extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder vacuum to get the crude product, which was purified by flashcolumn chromatography (15-17% ethyl acetate-petroleum ether as eluent)to get product (ethyl N-benzyl-N-methylglycinate) as a yellow liquid.Yield: 66%.

ES-MS [M+H]⁺: 208.2; Rt=1.27 min (Method B).

¹H NMR (400 MHz, CDCl₃) δ: 7.35-7.30 (m, 5H), 7.27-7.26 (m, 1H),4.20-4.16 (m, 2H), 3.67 (s, 2H), 3.25 (s, 2H), 2.38 (s, 3H), 1.26 (t,J=5.6 Hz, 3H).

General Procedure I

A mixture of an aromatic amine (ex: p-toluidine) (1 eq) anddicyandiamide (1 eq) in 3M hydrogen chloride (aq) (1 eq) was heated at90° C. for 16 h. After reaction completion, the mixture was cooled toroom temperature and during this process a solid compound precipitate(in some cases, the crude compound was co-distilled with toluene (3×).The crude was collected by vacuum filtration and washed with cold waterand triturated with ethyl acetate and diethyl ether to give the compoundas hydrochloride salt (ex: p-tolylbiguanide hydrochloride).

In some cases, the intermediate salt was then added to a mixture ofmethanol and methanolic sodium methoxide (25% solution, 12 mmol), andthe mixture was stirred at room temperature for 1 h. Followingfiltration, the filtrate was evaporated under vacuum and the precipitatewas re-dissolved in hot ethanol. Further precipitate was removed byfiltration, then ethanol was evaporated under vacuum and the resultingresidue was collected and dried to give the desired product (ex:N(1)-(4-Methylphenyl)biguanide).

Intermediate 2 N(1)-(4-Methylphenyl)biguanide

Yield: 86%.

HPLC-MS [M+H]⁺: 191; Rt=1.03 min (Method C).

Intermediate 3 N(1)-(4-Bromophenyl)-1-biguanide hydrochloride

Yield: 59%.

ES-MS [M+H-36.5]⁺: 256; Rt=1.36 min (Method B).

¹H NMR (500 MHz, MeOD) δ: 7.46-7.44 (m, 2H), 7.31-7.29 (m, 2H).

Intermediate 4 N(1)-(4-Methoxyphenyl)biguanide hydrochloride

Yield: 90%.

ES-MS [M+H-36.5]⁺: 208.2; Rt=0.47 min (Method B).

Intermediate 5 N(1)-β-Methylphenyl)biguanide hydrochloride

Yield: 60%.

ES-MS [M+H-36.5]⁺: 192; Rt=1.14 min (Method B).

Intermediate 6 N(1)-β-Bromophenyl)biguanide hydrochloride

Yield: 42%.

ES-MS [M+H-36.5]⁺: 255.01; Rt=1.32 min (Method B).

Intermediate 7 N(1)-β-Methoxyphenyl)biguanide hydrochloride

Yield: 76%.

ES-MS [M+H-36.5]⁺: 208; Rt=1.22 min (Method A).

Intermediate 8 N(1)-(2-Methoxyphenyl)biguanide hydrochloride

Yield: 66%.

ES-MS [M+H-36.5]⁺: 208.2; Rt=1.10 min (Method A).

General Procedure II

Freshly prepared appropriate biguanide (ex: p-tolylbiguanide) (1 eq) inmethanol (19 mL/mmol) was placed in a Schlenk. An appropriate ester (ex:ethyl N-methyl-N-phenylglycinate) (1 eq) was added and the mixture wasstirred at 40° C. or 90° C. for 16 h. The resultant crude was purifiedby flash column chromatography (hexane/acetate ordichloromethane/methanol) to obtain the desired product (ex:6-((methyl(phenyl)amino)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine).

Example 16-((Methyl(phenyl)amino)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine

Yield: 9%.

HPLC-MS [M+H]⁺: 321; Rt=2.72 min (Method C).

¹H NMR (400 MHz, CDCl₃) δ: 7.28 (s, 2H), 7.15 (ddd, J=7.3, 5.9, 2.3 Hz,2H), 7.00 (d, J=7.4 Hz, 2H), 6.84 (s, 1H), 6.71 (dd, J=8.8, 0.9 Hz, 2H),6.65 (td, J=7.3, 1.0 Hz, 1H), 5.04 (s, 2H), 4.26 (s, 2H), 3.07 (s, 3H),2.24 (s, 3H).

Example 2N²-(4-Methoxyphenyl)-6-((methyl(phenyl)amino)methyl)-1,3,5-triazine-2,4-diamine

Yield: 6%.

HPLC-MS [M+H]⁺: 337; Rt=2.43 min (Method C).

¹H NMR (400 MHz, CDCl₃) δ: 7.24 (d, J=20.0 Hz, 2H), 7.18-7.13 (m, 2H),6.79 (s, 1H), 6.75 (s, 2H), 6.72-6.68 (m, 2H), 6.67-6.62 (m, 1H), 5.05(s, 2H), 4.25 (s, 2H), 3.72 (s, 3H), 3.05 (s, 3H).

Example 3N²-β-Methoxyphenyl)-6-((methyl(phenyl)amino)methyl)-1,3,5-triazine-2,4-diamine

Yield: 21%.

HPLC-MS [M+H]⁺: 337; Rt=2.65 min (Method C).

¹H NMR (400 MHz, CDCl₃) δ: 7.19 (d, J=2.1 Hz, 1H), 7.17-7.13 (m, 2H),7.10 (t, J=8.5 Hz, 1H), 6.97 (s, 1H), 6.93 (dd, J=8.2, 1.4 Hz, 1H), 6.69(dt, J=3.5, 1.8 Hz, 2H), 6.64 (tt, J=5.0, 2.5 Hz, 1H), 6.57-6.51 (m,1H), 5.16 (s, 2H), 4.26 (s, 2H), 3.70 (s, 3H), 3.07 (s, 3H).

General Procedure III

To a stirred solution of the appropriate biguanide hydrochloride salt(ex: p-tolylbiguanide) (1.0 eq) in methanol (2.4 mL/mmol) was addedsodium methoxide (1.0 eq, 25 wt % in methanol) at room temperature andit was stirred for 30 min. The appropriate ester was added to thereaction mixture (ex: ethyl N-benzyl-N-methylglycinate) (1.2 eq) andheated to 70° C. for 18 h. After reaction completion, the reactionmixture was poured into cold water and the organic product was extractedwith ethyl acetate. Organic extracts were dried over anhydrous sodiumsulfate and the solvent was evaporated under vacuum to get the crudemixture. The crude product was purified by flash column chromatography(ethyl acetate-petroleum ether as eluent) to get the desired triazineproduct (ex:6-((benzyl(methyl)amino)methyl)-N²-p-tolyl-1,3,5-trizine-2,4-diamine).

Example 46-((Benzyl(methyl)amino)methyl)-N²-p-tolyl-1,3,5-trizine-2,4-diamine

Yield: 14%.

ES-MS [M+H]⁺: 335.2; Rt=1.59 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.35 (br s, 1H), 7.66 (d, J=8.0 Hz, 2H),7.36-7.30 (m, 4H), 7.26-7.22 (m, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.00 (brs, 2H), 3.63 (s, 2H), 3.33 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H).

Example 56-((Benzyl(methyl)amino)methyl)-N²-(4-bromophenyl)-1,3,5-triazine-2,4-diamine

Yield: 25%.

ES-MS [M+H]⁺: 399.1; Rt=1.63 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.62 (br s, 1H), 7.79 (d, J=8.8 Hz, 2H),7.41 (d, J=9.6 Hz, 2H), 7.36-7.29 (m, 4H), 7.26-7.22 (m, 1H), 7.14-7.04(m, 2H), 3.63 (s, 2H), 3.35 (s, 2H), 2.21 (s, 3H).

Example 66-((Benzyl(methyl)amino)methyl)-N²-(4-methoxyphenyl)-1,35-triazine-2,4-diamine

Yield: 3%.

ES-MS [M+H]⁺: 351.2; Rt=1.53 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.28 (br s, 1H), 7.66 (d, J=8.8 Hz, 2H),7.35-7.29 (m, 4H), 7.25-7.22 (m, 1H), 6.94 (br s, 2H), 6.83 (d, J=8.8Hz, 2H), 3.72 (s, 3H), 3.63 (s, 2H), 3.32 (s, 2H), 2.21 (s, 3H).

Example 76-((Benzyl(methyl)amino)methyl)-N²-m-tolyl-1,3,5-triazine-2,4-diamine

Yield: 8%.

ES-MS [M+H]⁺: 208.2; Rt=1.27 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.37 (br s, 1H), 7.63-7.59 (m, 2H),7.36-7.29 (m, 4H), 7.25-7.22 (m, 1H), 7.14-7.10 (m, 1H), 7.02 (br s,2H), 6.77 (d, J=7.6 Hz, 1H), 3.64 (s, 2H), 3.35 (s, 2H), 2.26 (s, 3H),2.22 (s, 3H).

Example 86-((Benzyl(methyl)amino)methyl)-N²-β-bromophenyl)-1,3,5-triazine-2,4-diamine

Yield: 15%.

ES-MS [M+H]⁺: 399.1; Rt=1.62 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.65 (s, 1H), 8.11 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.36-7.29 (m, 4H), 7.25-7.11 (m, 5H), 3.64 (s, 2H), 3.37 (s,2H), 2.23 (s, 3H).

Example 96-(Benzyl(methyl)amino)methyl)-N²-(3-methoxyphenyl)-1,3,5-triazine-2,4-diamine

Yield: 3%.

ES-MS [M+H]⁺: 351.2; Rt=1.55 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.43 (br s, 1H), 7.57 (s, 1H), 7.36-7.29(m, 5H), 7.25-7.22 (m, 1H), 7.12 (br s, 3H), 6.55-6.52 (m, 1H), 3.72 (s,3H), 3.63 (s, 2H), 3.54 (s, 2H), 2.21 (s, 3H).

Example 10 6-((Benzyl (methyl) amino)methyl)-N²-(2-methoxyphenyl)-1,3,5-triazine-2,4-diamine

Yield: 6.9%.

ES-MS [M+H]⁺: 351.2; Rt=1.56 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J=8.0 Hz, 1H), 7.87 (s, 1H),7.35-7.29 (m, 4H), 7.26-7.22 (m, 1H), 7.06-7.02 (m, 4H), 6.93-6.89 (m,1H), 3.83 (s, 3H), 3.63 (s, 2H), 3.34 (s, 2H), 2.21 (s, 3H).

General Procedure IV

To a stirred and degassed (with argon) solution of bromo phenyl triazine(ex:6-((benzyl(methyl)amino)methyl)-N²-(4-bromophenyl)-1,3,5-triazine-2,4-diamine)(1 eq), Zn(CN)₂ (2.05 eq) in dimethyl formamide (9 mL/mmol) at roomtemperature were added DavePhos (0.026 eq) and Pd(PPh₃)₄ (0.05 eq). Thereaction mixture was irradiated under microwave at 160° C. for 0.5 h.After reaction completion, the reaction mixture was cooled to roomtemperature and slowly poured into water and the organic product wasextracted with ethyl acetate. The organic layer was washed with water,brine solution and dried over anhydrous sodium sulfate. The solvent wasevaporated under vacuum to get the crude product, which was purified byflash column chromatography purification using 20% to 60% ethylacetate-petroleum ether as eluent to get the wanted product (ex:(4-((4-amino-6-((benzyl(methyl)amino)methyl)-1,3,5-triazin-2-yl)amino)benzonitrile).

Example 114-(4-Amino-6-((benzyl(methyl)amino)methyl)-1,3,5-triazin-2-ylamino)benzonitrile

Yield: 11%.

ES-MS [M+H]⁺: 346.2; Rt=1.53 min (Method B).

¹H NMR (500 MHz, DMSO-d₆) δ: 10.02 (s, 1H), 8.03 (d, J=8.5 Hz, 2H), 7.70(d, J=9.0 Hz, 2H), 7.30 (s, 7H), 3.60 (s, 2H), 3.39 (s, 2H), 2.22 (s,3H).

Example 123-(4-Amino-6-((benzyl(methyl)amino)methyl)-1,3,5-triazin-2-ylamino)benzonitrile

Yield: 8%.

ES-MS [M+H]⁺: 346.2; Rt=1.54 min (Method B).

¹H NMR (500 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.38 (s, 1H), 8.02-8.00 (m,1H), 7.48-7.45 (m, 1H), 7.40-7.39 (m, 1H), 7.36-7.30 (m, 4H), 7.26-7.24(m, 3H), 3.63 (s, 2H), 3.37 (s, 2H), 2.22 (s, 3H).

Intermediate 9 tert-butyl 4-(benzyl(methyl)amino)-3-oxobutanoate

To a stirring solution of t-butyl acetate (5.0 g, 43.4 mmol, 3.0 eq) intetrahydrofuran (25 mL) was added lithium diisopropylamide (2 M intetrahydrofuran) (24.63 mL, 49.2 mmol, 3.4 eq) at −78° C. under nitrogenatmosphere and stirred for 60 min at −78° C. To the reaction mixture wasadded a solution of compound ethyl N-benzyl-N-methylglycinate (3.0 g,14.5 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at −78° C. and stirred foranother 1 h. The reaction mixture was quenched with saturated ammoniumchloride solution and stirred for 10-15 min at room temperature. Theorganic product was extracted with ethyl acetate. The organic layer waswashed with water followed by brine solution. The organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure to afford crude compound tert-butyl4-(benzyl(methyl)amino)-3-oxobutanoate (4.0 g, 14.4 mmol). The crudeproduct was used for the next step without further purification. Yield:95%.

ES-MS [M+H]⁺: 278.2; Rt=1.52 min (Method B).

Intermediate 10 ethyl 4-(benzyl(methyl)amino)-3-oxobutanoate

In a sealed tube compound tert-butyl4-(benzyl(methyl)amino)-3-oxobutanoate (4.0 g, 14.4 mmol, 1.0 eq) wasdissolved in ethanol (25 mL). The reaction mixture was heated to 100° C.for 16 h. The reaction mixture was cooled to room temperature andsolvent was concentrated under reduced pressure to afford the residue.The residue was dissolved in ethyl acetate and the organic layer waswashed with water followed by brine. The organic layer was dried overanhydrous sodium sulfate and the solvent was concentrated under reducedpressure to afford crude mixture. The crude was purified by columnchromatography (silica gel 100-200 mesh; using 20% ethyl acetate inpetroleum ether) to get the compound ethyl4-(benzyl(methyl)amino)-3-oxobutanoate (1.3 g) as off white solid.Yield: 36%.

ES-MS [M+H]⁺: 250.2; Rt=1.36 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.35-7.24 (m, 5H), 4.21-4.14 (m, 2H), 3.58(s, 2H), 3.51 (s, 2H), 3.25 (s, 2H), 2.28 (s, 3H), 1.29-1.26 (t, 3H).

General Procedure V

Under nitrogen atmosphere, a mixture of the appropriate phenyl amine (1eq), wherein R¹ and R² are as defined above (ex: N-methylaniline),sodium bicarbonate (2 eq), the corresponding oxobutanone (2 eq) (ex:ethyl 4-chloro-3-oxobutanoate) and potassium iodide (2 eq) in dryacetonitrile (0.2 mL/mmol) was heated at 80° C. for 16 h. After coolingat room temperature, sodium thiosulfate saturated solution was added andthe organic layer was separated. The aqueous layer was extracted withethyl acetate (×3) and the combined organic layers were adjusted to pH=3with aqueous hydrochloric acid 1M. The aqueous phase was cleaned withethyl acetate (×2) and basified carefully with sodium hydroxide (1M)until pH=8. Ethyl acetate was added and organic layer was separated,dried over magnesium sulfate, filtrated, and concentrated under vacuum.The crude was purified by flash column chromatography(dichloromethane/methanol) to obtain the desired product (ex: ethyl4-(methyl(phenyl)amino)-3-oxobutanoate).

Intermediate 11 Ethyl 4-(methyl(phenyl)amino)-3-oxobutanoate

Yield: 22%.

HPLC-MS [M+H]⁺: 236; Rt=2.93 min (Method C).

Intermediate 12 Ethyl 4-(3,4-dihydroquinolin-1 (2H)-yl)-3-oxobutanoate

Yield: 51%

HPLC-MS [M+H]⁺: 262; Rt=3.15 min (Method C).

General Procedure VI

The appropriate amino oxobutanoate (1.1 eq), wherein R¹, R², and n areas defined above, (ex: ethyl 4-(methyl(phenyl)amino)-3-oxobutanoate),guanidine hydrochloride (1 eq) and potassium carbonate (1.1 eq) inethanol were stirred at reflux temperature for 16 h. After cooling, theappeared precipitate was filtered off and the resultant crude waspurified by flash column chromatography (dichloromethane/methanol) toobtain the desired pyrimidine product (ex:2-amino-6-((methyl(phenyl)amino)methyl)pyrimidin-4-ol).

Intermediate 13 2-Amino-6-((methyl(phenyl)amino)methyl)pyrimidin-4-ol

Yield: 74%.

HPLC-MS [M+H]⁺: 231; Rt=1.80 min (Method C).

Intermediate 14 2-Amino-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4-ol

Yield: 37%.

HPLC-MS [M+H]⁺: 257; Rt=2.05 min (Method C).

Intermediate 15 2-amino-6-((benzyl(methyl)amino)methyl)pyrimidin-4-ol

In a sealed tube 30% sodium methoxide in methanol (6 mL) was added to astirred solution of compound ethyl4-(benzyl(methyl)amino)-3-oxobutanoate (1.2 g, 4.8 mmol, 1.0 eq) inethanol (10 mL) and stirred for 10 min at room temperature. Guanidinehydrochloride was added to (0.91 g, 9.6 mmol, 2 eq) the reaction mixtureat room temperature. The reaction mixture was heated to 100° C. understirring condition for 16 h. Reaction mixture was cooled to roomtemperature and the solvent was evaporated under reduced pressure to getthe crude product. The crude product was purified by reverse phase flashcolumn chromatography using 0.1% formic acid in water and acetonitrileas eluent to get pure compound2-amino-6-((benzyl(methyl)amino)methyl)pyrimidin-4-ol (0.9 g, 3.7 mmol).Yield: 77%.

ES-MS [M+H]⁺: 245.2; Rt=1.042 min (Method B).

General Procedure VII

A heterogeneous solution of the corresponding pyrimidin-4-ol (1 eq) (ex:2-amino-6-((methyl(phenyl)amino)methyl)pyrimidin-4-ol) in phosphorylchloride (10 eq) was heated to reflux temperature during 1 h. Thereaction mixture was cooled and concentrated under vacuum to removeexcess of phosphoryl chloride. The residue was taken-up intodichloromethane, neutralized and subsequently basified carefully withsodium hydroxide (1M) until pH=8. The organic layer was separated,washed with water, dried over magnesium sulfate and concentrated undervacuum. The resultant crude was purified by flash column chromatography(dichloromethane/methanol) to obtain the desired product (ex:4-chloro-6-((methyl(phenyl)amino)methyl)pyrimidin-2-amine).

Intermediate 164-Chloro-6-((methyl(phenyl)amino)methyl)pyrimidin-2-amine

Yield: 7%.

HPLC-MS [M+H]⁺: 249/251; Rt=2.93 min (Method C).

Intermediate 17 4-Chloro-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-2-amine

Yield: 52%.

HPLC-MS [M+H]⁺: 275; Rt=3.15 min (Method C).

General Procedure VIII

The appropriate chloride (1 eq) (ex:4-chloro-6-((methyl(phenyl)amino)methyl)-pyrimidin-2-amine) and thecorresponding aromatic amine (2 eq) (ex: p-toluidine) were stirred at140° C. for 1-5 h. The resultant crude was purified by flash columnchromatography (dichloromethane/methanol) to obtain the desired product(ex:6-((methyl(phenyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine).

Example 136-((Methyl(phenyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine

Yield: 50%.

HPLC-MS [M+H]⁺: 320; Rt=2.35 min (Method C).

¹H NMR (400 MHz, CDCl₃) δ: 7.23 (dd, J=8.8, 7.3 Hz, 2H), 7.07 (dd,J=20.5, 8.4 Hz, 4H), 6.74 (t, J=7.2 Hz, 1H), 6.68 (d, J=7.9 Hz, 2H),6.40 (s, 1H), 5.93 (s, 1H), 4.30 (s, 2H), 3.49 (s, 3H), 2.30 (s, 3H).

Example 146-((3,4-Dihydroquinolin-1(2H)-yl)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine

Yield: 10%.

HPLC-MS [M+H]⁺: 346; Rt=2.38 min (Method C).

¹H NMR (400 MHz, CDCl₃) δ: 7.37 (s, 2H), 7.10 (d, J=8.3 Hz, 2H), 6.93(t, J=8.2 Hz, 2H), 6.64 (t, J=7.1 Hz, 1H), 6.32-6.11 (m, 2H), 4.22 (s,2H), 3.46-3.19 (m, 2H), 2.74 (t, J=6.2 Hz, 2H), 2.29 (d, J=10.2 Hz, 3H),2.06-1.91 (m, 2H).

General Procedure IX

To a stirred solution of a chloride compound (ex:4-((benzyl(methyl)amino)methyl)-6-chloropyrimidin-2-amine) (1.0 eq) in1-butanol (13 mL/mmol) were added the corresponding aniline (ex.o-anisidine) (2.0 eq), sulfuric acid (catalytic, 2 drops) at roomtemperature and heated to 100° C. for 16 h. After completion of thereaction, the reaction mixture was allowed to cool to room temperatureand diluted with water and basified with saturated sodium bicarbonate(˜pH=8). The aqueous layer was extracted twice with ethyl acetate, driedover anhydrous sodium sulfate and solvent was evaporated under reducedpressure to get crude compound. The crude was purified by flash columnchromatography instrument using 2% to 15% methanol in dichloromethane aseluent to get the product (ex: 6-((benzyl (methyl) amino)methyl)-N⁴-(2-methoxyphenyl) pyrimidine-2,4-diamine).

Example 156-((benzyl(methyl)amino)methyl)-N⁴-(2-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 7% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 350.32; Rt=1.96 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.15 (s, 1H), 8.06-8.04 (d, J=7.6 Hz, 1H),7.34-7.24 (m, 5H), 7.03-7.01 (m, 2H), 6.92-6.88 (m, 1H), 6.34 (s, 1H),6.05 (br s, 2H), 3.80 (s, 3H), 3.51 (s, 2H), 3.24 (s, 2H), 2.12 (s, 3H).

Example 16 6-((benzyl(methyl)aminomethyl)-N⁴-m-tolylpyrimidine-2,4-diamine

Yield: 4% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 334.3; Rt=2.31 min (Method F).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.98 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47(s, 1H), 7.37-7.31 (m, 4H), 7.28-7.26 (m, 1H), 7.15-7.11 (m, 1H), 6.75(d, J=7.6 Hz, 1H), 6.27 (s, 1H), 6.13 (br s, 2H), 3.53 (s, 2H), 3.25 (s,2H), 2.28 (s, 3H), 2.14 (s, 3H).

Example 176-((benzylmethyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 7% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 350.32; Rt=1.96 min (Method E).

¹H NMR (400 MHz, DMSO-d₆): 9.07 (s, 1H), 7.45-7.44 (m, 1H), 7.38-7.31(m, 4H), 7.28-7.20 (m, 2H), 7.16-7.12 (m, 1H), 6.52-6.49 (m, 1H), 6.28(s, 1H), 6.16 (br s, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 3.26 (s, 2H), 2.15(s, 3H).

Example 186-((benzyl(methyl)amino)methyl)-N⁴-(4-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 6% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 350.40; Rt=2.18 min (Method F).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 7.55 (d, J=9.2 Hz, 2H),7.34-7.24 (m, 5H), 6.87-6.83 (m, 2H), 6.19 (s, 1H), 6.04 (br s, 2H),3.72 (s, 3H), 3.52 (s, 2H), 3.24 (s, 2H), 2.13 (s, 3H).

Example 194-(2-amino-6-((benzyl(methyl)amino)methyl)pyrimidin-4-ylamino)benzonitrile

Yield: 7% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 345.40; Rt=1.91 min (Method G).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.63 (s, 1H), 7.98-7.96 (m, 2H), 7.67-7.65(m, 2H), 7.38-7.26 (m, 5H), 6.38 (s, 2H), 6.35 (s, 2H), 3.55 (s, 2H),3.29 (s, 2H), 2.15 (s, 3H).

Example 206-((benzyl(methyl)amino)methyl)-N⁴-β-chlorophenyl)pyrimidine-2,4-diamine

Yield: 5% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 354.24; Rt=2.11 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.28 (s, 1H), 7.92 (s, 1H), 7.63 (d, J=8.4Hz, 1H), 7.36-7.24 (m, 6H), 6.95 (d, J=7.6 Hz, 1H), 6.29-6.26 (m, 3H),3.54 (s, 2H), 3.27 (s, 2H), 2.15 (s, 3H).

Example 216-((benzyl(methyl)amino)methyl)-N⁴-(4-chlorophenyl)pyrimidine-2,4-diamine

Yield: 4% (over 2 steps from intermediate 16).

ES-MS [M+H]⁺: 354.36; Rt=2.12 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (s, 1H), 7.79-7.77 (m, 2H), 7.36-7.34(m, 4H), 7.28-7.26 (m, 3H), 6.27 (s, 1H), 6.21 (br s, 2H), 3.54 (s, 2H),3.26 (s, 2H), 2.14 (s, 3H).

Intermediate 18 2-(benzyl(methyl)amino)acetonitrile

To a stirring solution of N-methyl-1-phenylmethanamine (5.0 g, 41.3mmol, 1.0 eq) in dichloromethane (50 mL) was addedN,N-Diisopropylethylamine (16.5 mL, 98.4 mmol, 2.4 eq) under nitrogenatmosphere. To the reaction mixture was added 2-bromo acetonitrile (5.44g, 45.9 mmol, 1.1 eq) drop wise at 0° C. The reaction mixture wasallowed to come to room temperature and stirred for 16 h. Reactionmixture was quenched with ice water and then the dichloromethane layerwas separated. The organic layer was washed with water followed bybrine. The organic layer was dried over anhydrous sodium sulfate andsolvent was concentrated under reduced pressure to afford crude product.Crude product was purified by column chromatography (silica gel 100-200mesh; using 10% ethyl acetate in petroleum ether) to get the product2-(benzyl (methyl) amino) acetonitrile (5.0 g) as yellow liquid.

Yield: 75%.

ES-MS [M+H]⁺: 161.2; Rt=1.70 min (Method B).

¹H NMR (400 MHz, CDCl₃) δ: 7.4-7.25 (m, 5H), 3.60 (s, 2H), 3.45 (s, 2H),3.43 (s, 3H).

Intermediate 19 2-(benzyl(methyl)amino)acetimidamide

To a stirred suspension of ammonium chloride (0.33 g, 6.2 mmol, 2.0 eq)in toluene at 0° C. was added trimethyl aluminum (2.0 M in toluene)(3.15 mL, 6.2 mmol, 2.0 eq) and stirred at room temperature for 1 h. Tothe reaction mixture was added a solution of compound2-(benzyl(methyl)amino)acetonitrile (0.5 g, 3.1 mmol, 1.0 eq) in tolueneand heated to 110° C. for 16 h. After completion of the reaction, thereaction mixture was cooled to room temperature and slowly poured intothe emulsion of silica (˜3.0 g) in chloroform at 0° C. The mixture wasstirred for 30 min and filtered. The silica bed was washed thoroughlywith chloroform\methanol\aqueous ammonia (40:10:1 v/v/v). The combinedfiltrate was evaporated under reduced pressure and co-distilled withtoluene to get the crude compound 2-(benzyl(methyl)amino)acetimidamide(0.5 g) which was used for the next step without further purification.Yield: 90%.

ES-MS [M+H]⁺: 178.2; Rt=1.679 min (Method A).

Intermediate 20 2-((benzyl(methyl)amino)methyl)pyrimidine-4,6-diol

To a stirred solution of compound 2-(benzyl(methyl)amino)acetimidamide(0.5 g, 2.8 mmol, 1.0 eq) and diethylmalonate (0.5 mL, 0.54 mmol, 1.2eq) in methanol was added 30% sodium methoxide in methanol (0.76 mL, 4.2mmol, 1.5 eq) at room temperature and heated to 70° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was cooled to roomtemperature and concentrated under reduced pressure to get the crudeproduct. The crude product was purified by reverse phase purification inflash column chromatography using 0.01 M aqueous formic acid andmethanol as eluent to get compound2-((benzyl(methyl)amino)methyl)pyrimidine-4,6-diol as thick yellow gummysolid. Yield: 36% (over 2 steps from intermediate 18).

ES-MS [M+H]⁺: 246.1; Rt=1.331 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 12.0-11.75 (br s, 2H), 7.41-7.24 (m, 5H),5.16 (s, 1H), 3.63-3.60 (m, 2H), 3.45 (s, 2H), 2.16-2.15 (m, 3H).

Intermediate 21N-benzyl-1-(4,6-dichloropyrimidin-2-yl)-N-methylmethanamine

Phosphoryl chloride (0.6 mL, 1 g, 6.4 mmol, 2.6 eq) was added tocompound 2-((benzyl(methyl)amino)methyl)pyrimidine-4,6-diol (0.6 g, 2.4mmol, 1.0 eq) and heated to 100° C. for 3 h. After completion of thereaction, the reaction mixture was evaporated under reduced pressure andco-distilled twice with toluene to get the crude compoundN-benzyl-1-(4,6-dichloropyrimidin-2-yl)-N-methylmethanamine as browncolor liquid (0.6 g). The crude was used directly to next step withoutfurther purification. Yield: 89%.

ES-MS [M+H]⁺: 282.1; Rt=1.51 min (Method B).

Intermediate 222-((benzyl(methyl)amino)methyl)-6-chloro-N-(p-tolyl)pyrimidin-4-amine

To a stirred solution of compoundN-benzyl-1-(4,6-dichloropyrimidin-2-yl)-N-methylmethanamine (0.6 g, 2.1mmol, 1.0 eq) in concentrated hydrochloric acid (0.192 mL) and water(1.92 mL) at room temperature were added p-toluidine (0.258 g, 2.41mmol, 1.0 eq), sodium iodide (0.367 g, 2.41 mmol, 1.0 eq) and heated to100° C. for 16 h. The reaction mixture was allowed to cool to roomtemperature and basified with saturated sodium bicarbonate (˜pH=8) andthe organic product was extracted into ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure to get the crude mixture. The crude was purifiedby flash column chromatography using 10% to 60% ethyl acetate inpetroleum ether as eluent to get compound2-((benzyl(methyl)amino)methyl)-6-chloro-N-(p-tolyl)pyrimidin-4-amine(0.43 g) as pale brown thick liquid. Yield: 50% (over 2 steps fromintermediate 20).

ES-MS [M+H]⁺: 353.2; Rt=1.69 min (Method B).

¹H NMR (500 MHz, CDCl₃) δ: 7.39-7.13 (m, 9H), 7.00 (br s, 1H), 6.51 (s,1H), 3.72-3.66 (m, 2H), 3.61-3.56 (m, 2H), 2.36 (s, 6H).

Intermediate 23 Tert-butyl(2-((benzyl(methyl)amino)methyl)-6-(p-tolylamino)pyrimidin-4-yl)carbamate

To a stirred and degassed solution of2-((benzyl(methyl)amino)methyl)-6-chloro-N-(p-tolyl)pyrimidin-4-amine(0.5 g, 1.42 mmol, 1.0 eq), tert-butyl carbamate (0.332 g, 2.8 mmol, 2.0eq) in 1,4-dioxane (6 mL) were added cesium carbonate (1.38 g, 4.2 mmol,3.0 eq) XPhos (0.033 g, 0.07 mmol, 0.05 eq), Pd₂(dba)₃ (0.13 g, 0.142mmol, 0.1 eq) and heated to 90° C. for 16 h. After completion of thereaction, the reaction mixture was allowed to cool to room temperatureand diluted with water and the organic product was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andsolvent was evaporated under reduced pressure. The crude was purified byflash column chromatography using 20% to 60% ethyl acetate in petroleumether as eluent to get the product tert-butyl(2-((benzyl(methyl)amino)methyl)-6-(p-tolylamino)pyrimidin-4-yl)carbamate(0.38 g) as pale yellow thick liquid. Yield: 61%.

ES-MS [M+H]⁺: 434.3; Rt=1.84 min (Method B).

Example 222-((Benzyl(methyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-4,6-diamine

A solution of compound tert-butyl2-((benzyl(methyl)amino)methyl)-6-(p-tolylamino)pyrimidin-4-ylcarbamate(0.38 g, 1 eq) in 4N hydrochloric acid in 1,4-dioxane (10 eq) wasstirred at room temperature for 16 h. After completion of the reaction,the reaction mixture was evaporated under reduced pressure. The crudewas basified with saturated sodium bicarbonate and the product wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and evaporated. The crude was purified bypreparative HPLC (reverse phase) to get the product2-((benzyl(methyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-4,6-diamine aspale yellow solid.

Yield: 5% (over 2 steps from intermediate 22).

ES-MS [M+H]⁺: 334.44; Rt=4.44 min (Method D).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.72 (s, 1H), 7.41 (d, J=8.4 Hz, 2H),7.37-7.29 (m, 4H), 7.25-7.23 (m, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.24 (s,2H), 5.64 (s, 1H), 3.62 (s, 2H), 3.37 (s, 2H), 2.24 (s, 3H), 2.19 (s,3H).

Intermediate 24 Methyl2-chloro-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylate

A mixture of compound methyl 2,6-dichloropyrimidine-4-carboxylate (5.0g, 24.2 mmol, 1.0 eq), tert-octylamine (6.71 mL, 36.4 mmol, 1.5 eq) andN,N-diisopropylethylamine (6.71 mL, 36.4 mmol, 1.5 eq) intetrahydrofuran (5 mL) was stirred at room temperature for 24 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand the organic product was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to get crude product. The crude waspurified by flash column chromatography column using 10% to 40% ethylacetate in petroleum ether as eluent to get methyl2-chloro-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylate(3.0 g) as white solid. Yield: 41%.

ES-MS [M+H]⁺: 300.2; Rt=2.167 min (Method B).

Intermediate 25N-benzyl-2-chloro-N-methyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide

To a stirred solution of compound methyl2-chloro-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylate(0.5 g, 1.67 mmol, 1.0 eq), N-methylbenzylamine (0.202 g, 1.67 mmol, 1.0eq) in tetrahydrofuran (10 mL) at room temperature was added1,5,7-triazabicyclo[4.4.0]dec-5-ene (69.6 mg, 0.5 mmol, 0.3 eq) andstirred for 3 h at room temperature. After completion of the reaction,the reaction mixture was diluted with water and the organic product wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by flash columnchromatography column using 10% to 50% ethyl acetate in petroleum etheras eluent to get compoundN-benzyl-2-chloro-N-methyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide(0.21 g) as a pale yellow thick liquid. Yield: 32%.

ES-MS [M+H]⁺: 289.3; Rt=2.281 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.74-7.73 (d, J=6.4 Hz, 1H), 7.40-7.25 (m,5H), 6.55 (s, 1H), 4.61 (s, 1H), 4.50 (s, 1H), 2.83-2.82 (m, 3H), 3.37(s, 2H), 1.88-1.86 (m, 2H), 1.42-1.41 (m, 6H), 0.92-0.88 (m, 9H).

Intermediate 266-((Benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine

To a stirred solution of compoundN-benzyl-2-chloro-N-methyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide(0.21 g, 0.5 mmol, 1.0 eq) in tetrahydrofuran at 0° C. was added boranedimethyl sulfide complex (0.16 mL, 1.5 mmol, 3.0 eq) and stirred at 70°C. for 4 h. The reaction mixture was allowed to cool to 0° C., quenchedwith 2 N hydrochloric acid, basified with saturated sodium bicarbonatesolution (pH-8) and the organic product was extracted intodichloromethane. The organic layer was dried over anhydrous sodiumsulfate and solvent was evaporated under reduced pressure to get crudeproduct. The crude product was purified by flash column chromatographycolumn using 10% to 50% ethyl acetate in petroleum ether as eluent toget compound6-((benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine(0.08 g) as thick liquid. Yield: 39%.

ES-MS [M+H]⁺: 375.3; Rt=1.90 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.37-7.11 (m, 10H), 3.64 (s, 2H), 3.37 (s, 2H), 2.22 (s, 3H).

Intermediate 276-((Benzyl(methyl)amino)methyl)-N²-p-tolyl-N⁴-(2,4,4-trimethylpentan-2-yl)pyrimidine-2,4-diamine

To a stirred solution of compound6-((benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine(0.08 g, 0.2 mmol, 1.0 eq) in 1-butanol (0.2 mL) at room temperaturewere added p-toluidine (0.04 g, 0.4 mmol, 2.0 eq), catalytic sulfuricacid (2 drops) and heated to 110° C. for 16 h. After completion of thereaction, the reaction mixture was cooled to room temperature and slowlybasified with saturated sodium bicarbonate and the organic product wasextracted into ethyl acetate. The organic layer was dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by flash columnchromatography using 10% to 60% ethyl acetate in petroleum ether aseluent to get compound6-((benzyl(methyl)amino)methyl)-N²-p-tolyl-N⁴-(2,4,4-trimethylpentan-2-yl)pyrimidine-2,4-diamine(0.07 g) as pale brown thick liquid. Yield: 78%.

ES-MS [M+H]⁺: 446.4; Rt=2.028 min (Method B).

Example 236-((benzyl(methyl)amino)methyl)-N²-p-tolylpyrimidine-2,4-diamine

To a stirred solution of compound6-((benzyl(methyl)amino)methyl)-N²-p-tolyl-N⁴-(2,4,4-trimethylpentan-2-yl)pyrimidine-2,4-diaminein dichloromethane (3 mL) at room temperature was added trifluoro aceticacid (7 eq) and heated to 40° C. for 16 h. The reaction mixture wasevaporated completely to get the residue which was basified withsaturated sodium bicarbonate and the organic product was extracted intodichloromethane. The organic layer was dried over anhydrous sodiumsulfates and solvent was evaporated under reduced pressure. The crudeproduct was purified by flash column chromatography using 20% to 60%ethyl acetate in petroleum ether as eluent to get6-((benzyl(methyl)amino)methyl)-N²-p-tolylpyrimidine-2,4-diamine (0.04g) as pale yellow solid. Yield: 16%.

ES-MS [M+H]⁺: 334.2; Rt=1.615 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 7.57-7.41 (m, 9H), 7.10 (d,J=8.4 Hz, 1H), 6.03 (s, 1H), 4.14 (s, 2H), 3.84 (s, 2H), 2.55 (s, 2H),2.26 (s, 3H).

Intermediate 28 4,6-dichloropicolinic acid

Lithium hydroxide monohydrate (1.46 g, 34.9 mmol) was added to asolution of methyl 4,6-dichloropicolinate (4.8 g, 23.3 mmol) inmethanol:water (100 mL, 1:0.1 v/v) at 0° C. The reaction mixture waswarmed to room temperature and stirred for 16 h. The reaction mixturewas concentrated under reduced pressure to get crude product which wasdiluted with water. The crude was acidified by 2N hydrochloric acid at0° C. to get white precipitate. The precipitate was filtered and driedunder vacuum to get 3.0 g of 4,6-dichloropicolinic acid. Yield: 67%.

ES-MS [M+H]⁺: 190.02; Rt=1.55 min (Method B).

Intermediate 29 N-benzyl-4,6-dichloro-N-methylpicolinamide

50% Propylphosphonic anhydride solution in ethyl acetate (20.0 mL, 31.5mmol) was added to a suspension of 4,6-dichloropicolinic acid (3.0 g,15.7 mmol), N-methyl-1-phenylmethanamine (2.8 g, 23.6 mmol) anddiisopropylethylamine (13.5 mL, 78.9 mmol) in dichloromethane (50 mL) at0° C. The reaction mixture was warmed to room temperature and stirredfor 16 h. The reaction mixture was quenched with saturated sodiumbicarbonate solution, the organic product was extracted withdichloromethane (3×40 mL). The combined organic extracts were washedwith water, brine, dried over anhydrous sodium sulfate and solvent wasevaporated under reduced pressure to get crude product. The crudeproduct was purified by column chromatography (silica gel 230-400 mesh,30% ethyl acetate in petroleum ether as eluent) to afford 3.5 g ofN-benzyl-4,6-dichloro-N-methylpicolinamide as pale yellow oil. Yield:75%.

ES-MS [M+H]⁺: 295.1; Rt=1.99 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.93-7.90 (m, 1H), 7.85-7.80 (m, 1H),7.40-7.27 (m, 5H), 4.67 (s, 1H), 4.49 (s, 1H), 2.84 (d, J=14 Hz, 3H).

Intermediate 30N-benzyl-1-(4,6-dichloropyridin-2-yl)-N-methylmethanamine

Borane dimethyl sulphide complex solution (33.2 mL, 66.4 mmol; 2.0M intetrahydrofuran) was added to the solution ofN-benzyl-4,6-dichloro-N-methylpicolinamide (3.1 g, 11.0 mmol) intetrahydrofuran (70 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 16 h. The reaction mixture was cooled to 0°C. and quenched with saturated sodium bicarbonate solution. The organicproduct was extracted with dichloromethane (3×60 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by column chromatography(silica gel 230-400 mesh, 10% ethyl acetate in petroleum ether aseluent) to get 2.1 g of N-benzyl-4,6-dichloro-N-methylpicolinamide asyellow oil. Yield: 71%.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.85 (d, J=1.6 Hz, 1H), 7.73 (d, J=2 Hz,1H), 7.66-7.58 (m, 2H), 7.42-7.33 (m, 3H), 4.03-3.99 (m, 2H), 3.78 (d,J=12.4 Hz, 1H), 3.62-3.57 (m, 1H), 2.47 (s, 3H).

Intermediate 31 2-((benzyl(methy)amino)methyl)-6-chloropyridin-4-amine

Sodium azide (1.38 g, 21.3 mmol) was added to a solution ofN-benzyl-1-(4,6-dichloropyridin-2-yl)-N-methylmethanamine (2.0 g, 7.1mmol) in anhydrous dimethylformamide (50 mL) at 0° C. The reactionmixture was warmed to room temperature and heated at 90° C. for 24 h.After completion of reaction (monitored by TLC), reaction mixture wasquenched with water and organic product was extracted using ethylacetate (3×50 mL). The combined organic extracts were washed with water,brine, dried over anhydrous sodium sulfate and solvent was evaporatedunder reduced pressure to get crude product. The crude product wasdissolved in methanol (50 mL) and sodium borohydride (0.5 g, 14.2 mmol)was added at 0° C. The reaction mixture was warmed to room temperatureand stirred for 2 h. After completion of reaction, solvent wasevaporated under reduced pressure to obtain residue which was dilutedwith water and extracted using ethyl acetate (3×60 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by column chromatography(silica gel 230-400 mesh, 70% ethyl acetate in petroleum ether aseluent) to get 1.0 g of2-((benzyl(methyl)amino)methyl)-6-chloropyridin-4-amine as yellow oil.Yield: 53%.

ES-MS [M+H]⁺: 262.1; Rt=1.44 min (Method B).

¹H NMR (400 MHz, CDCl₃) δ: 7.37-7.30 (m, 5H), 7.24-7.22 (m, 1H), 6.74(d, J=2.0 Hz 1H), 6.42 (d, J=2.0 Hz, 1H), 4.22 (br s, 2H), 3.58 (s, 2H),3.54 (s, H), 2.23 (s, 3H).

Example 246-((benzyl(methyl)amino)methyl)-N²-(p-tolyl)pyridine-2,4-diamine

p-Toluidine (6.0 g) and2-((benzyl(methyl)amino)methyl)-6-chloropyridin-4-amine were mixed andheated at 200° C. for 16 h. After completion of starting material(monitored by TLC) the crude was purified by column chromatography(silica gel 230-400 mesh, 2-3% methanol in dichloromethane as eluent) toget 0.4 g of6-((benzyl(methyl)amino)methyl)-N-(p-tolyl)pyridine-2,4-diamine as darkbrown solid. The crude product was further purified by reverse phaseprep HPLC to afford 0.17 g of compound6-((benzyl(methyl)amino)methyl)-N²-(p-tolyl)pyridine-2,4-diamine. Yield:44%.

ES-MS [M+H]⁺: 333.33; Rt=1.61 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (s, 1H), 7.44 (d, J=8.4 Hz, 2H),7.38-7.31 (m, 4H), 7.26 (d, J=6.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.21(s, 1H), 5.83 (d, J=0.8 Hz, 1H), 5.68 (br s, 2H), 3.54 (s, 2H), 3.36 (s,2H), 2.21 (s, 3H), 2.14 (s, 3H).

Intermediate 32 N-benzyl-2,6-dichloro-N-methylisonicotinamide

50% Propylphosphonic anhydride solution in ethyl acetate (33.1 mL, 52.0mmol) was added to a suspension of 2,6-dichloroisonicotinic acid (5.0 g,26.0 mmol), N-methyl-1-phenylmethanamine (4.7 g, 39.0 mmol) anddiisopropylethylamine (22.3 mL, 130.0 mmol) in dichloromethane (80 mL)at 0° C. The reaction mixture was warmed to room temperature and stirredfor 16 h. The reaction mixture was quenched with saturated sodiumbicarbonate solution. The organic product was extracted withdichloromethane (3×50 mL). The combined organic extracts were washedwith water, brine, dried over anhydrous sodium sulfate and solvent wasevaporated under reduced pressure to get crude product. The crudeproduct was purified by column chromatography (silica gel 230-400 mesh,30% ethyl acetate in petroleum ether as eluent) to afford 6.0 g ofN-benzyl-2,6-dichloro-N-methylisonicotinamide as pale yellow oil. Yield:78%.

ES-MS [M+H]⁺: 295.1; Rt=1.99 min (Method B).

Intermediate 33N-benzyl-1-(2,6-dichloropyridin-4-yl)-N-methylmethanamine

Borane dimethyl sulphide complex solution (56.1 mL, 112.0 mmol; 2.0M intetrahydrofuran) was added to the solution ofN-benzyl-2,6-dichloro-N-methylisonicotinamide (5.5 g, 18.7 mmol) intetrahydrofuran (80 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 16 h. The reaction mixture was cooled to 0°C. and quenched with saturated sodium bicarbonate solution. The organicproduct was extracted with dichloromethane (3×60 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by column chromatography(silica gel 230-400 mesh, 10% ethyl acetate in petroleum ether aseluent) to get 2.8 g ofN-benzyl-1-(2,6-dichloropyridin-4-yl)-N-methylmethanamine as yellow oil.

Yield: 49%.

ES-MS [M+H]⁺: 281.1; Rt=1.61 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.51 (s, 2H), 7.35-7.32 (m, 4H), 7.28-7.24(m, 1H), 3.57 (m, 2H), 3.54 (s, 2H), 2.10 (s, 3H).

Intermediate 34 di-tert-butyl(4-((benzyl(methyl)amino)methyl)pyridine-2,6-diyl)dicarbamate

Cesium carbonate (1.39 g, 4.2 mmol) was added to a stirred solution ofN-benzyl-1-(2,6-dichloropyridin-4-yl)-N-methylmethanamine (0.4 g, 1.4mmol) and tert-butyl carbamate (0.5 g, 4.2 mmol) in 1,4-dioxane (10 mL).The reaction mixture was purged with argon for 10 min and addedPd₂(dba)₃ (0.065 g, 0.07 mmol) and XPhos (0.033 g, 0.07 mmol). Themixture was purged again with argon for 10 min. The reaction mixture washeated to 100° C. for 16 h in a sealed tube. After consumption ofstarting materials (monitored by TLC), reaction mixture was cooled toroom temperature and filtered through a pad of celite. The solvent wasconcentrated under reduced pressure to get 0.42 g of crude di-tert-butyl(4-((benzyl(methyl)amino)methyl)pyridine-2,6-diyl)dicarbamate as yellowoil which was used in the next step without purification. Yield: 66%.

ES-MS [M+H]⁺: 443.3; Rt=1.79 min (Method B).

Intermediate 35 4-((benzyl(methyl)amino)methyl)pyridine-2,6-diamine

4 N Hydrogen chloride in 1,4-dioxane (5 mL) was added to the solution ofdi-tert-butyl(4-((benzyl(methyl)amino)methyl)pyridine-2,6-diyl)dicarbamate (0.95mmol) in methanol (10 mL) at 0° C. The reaction mixture was warmed toroom temperature and stirred for 16 h. The reaction mixture wasconcentrated under reduced pressure to get crude product. The crude wasbasified with saturated sodium bicarbonate solution and the organicproduct was extracted with dichloromethane (3×30 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to get0.38 g of crude 4-((benzyl(methyl)amino)methyl)pyridine-2,6-diamine asyellow oil which was used for next step as such without anypurification. Yield: 95%.

ES-MS [M+H]⁺: 243.2; Rt=1.97 min (Method A).

Example 254-((benzyl(methyl)amino)methyl)-N²-(p-tolyl)pyridine-2,6-diamine

Copper(II)acetate (0.67 g, 3.7 mmol) was added to a solution of4-((benzyl(methyl)amino)methyl)pyridine-2,6-diamine (0.3 g, 1.2 mmol),4-methylphenyl boronic acid (0.25 g, 1.8 mmol) and triethylamine (0.4mL, 2.4 mmol) in dichloromethane (8 mL) at room temperature under oxygenatmosphere. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was filtered through a pad of celite and clearfiltrate was evaporated to get crude product. The crude product waspurified by column chromatography (silica gel 230-400 mesh, 2-4%methanol in dichloromethane as eluent) to get the impure product4-((benzyl(methyl)amino)methyl)-N²-(p-tolyl)pyridine-2,6-diamine whichwas further purified by reverse phase prep HPLC to afford 14 mg of4-((benzyl(methyl)amino)methyl)-N²-(p-tolyl)pyridine-2,6-diamine asoff-white solid. Yield: 3%.

ES-MS [M+H]⁺: 333.31; Rt=1.77 min (Method D).

¹H NMR (400 MHz, DMSO-d₆) δ: δ 8.37 (s, 1H), 7.50 (d, J=8.0 Hz, 2H),7.34-7.25 (m, 5H), 6.99 (d, J=8.0 Hz, 2H), 6.03 (s, 1H), 5.85 (s, 1H),5.57 (br s, 2H), 3.47 (s, 2H), 3.24 (s, 2H), 2.22 (s, 3H), 2.08 (s, 3H).

Example 26

6-((Benzyl(methyl)amino)methyl)-N²-(pyridin-3-yl)-1,3,5-triazine-2,4-diaminewas prepared according to the General Procedure III above:

Yield: 3%.

HPLC-MS [M−H]⁺: 320.2; Rt=1.23 min (Method B).

¹H NMR (500 MHz, DMSO-d₆) δ: 9.68 (br s, 1H), 8.96-8.95 (d, J=2.0 Hz,1H), 8.25-8.20 (m, 1H), 8.18-8.16 (m, 1H), 7.35-7.22 (m, 8H), 3.63 (s,2H), 3.36 (s, 2H), 2.22 (s, 3H).

Example 27

6-(((1,2,3,4-Tetrahydronaphthalen-2-yl)amino)methyl)-N-(p-tolyl)-1,3,5-triazine-2,4-diaminewas prepared according to the General Procedure III above:

Yield: 13%.

HPLC-MS [M+H]⁺: 361; Rt=2.07 min (Method A).

¹H NMR (400 MHz, CD₃OD) δ 7.49 (d, J=8.1 Hz, 2H), 7.17-7.04 (m, 6H),3.89 (s, 2H), 3.25-3.14 (m, 2H), 2.93-2.91 (m, 2H), 2.79-2.76 (m, 1H),2.30 (s, 3H), 2.25-2.21 (m, 1H), 1.75-1.73 (m, 1H).

General Procedure X

In a sealed tube, sodium methoxide (30%, 1.5 eq) in methanol (6 mL) andguanidine hydrochloride (1-1.5 eq) were added to a stirred solution ofthe appropriate amino oxobutanoate (prepared following literatureprocedures) (ex: ethyl 4-(benzyl(methyl)amino)-3-oxobutanoate) (1.0 eq)in ethanol (10 mL). The reaction mixture was heated to 90-100° C. understirring condition for 16 h. Reaction mixture was cooled to roomtemperature and the solvent was evaporated under reduced pressure to getthe crude product. The crude product was purified by flash columnchromatography (20% dichloromethane/methanol) or HPLC (0.1% formic acidin water/acetonitrile) to obtain the desired pyrimidine product (ex:2-amino-6-((benzyl(methyl)amino)methyl)pyrimidin-4-ol.

Intermediate 362-Amino-6-(((4-methoxybenzyl)(methyl)amino)methyl)pyrimidin-4-ol

Yield: 36%.

HPLC-MS [M+H]⁺: 275.15; Rt=0.23 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.5 (br s, 1H), 7.24-7.22 (m, 2H),6.90-6.85 (m, 4H), 5.61 (s, 1H), 3.72 (s, 3H), 3.44 (s, 2H), 3.11 (s,2H), 2.11 (s, 3H).

Intermediate 372-Amino-6-((methyl(3-methylbenzyl)amino)methyl)pyrimidin-4-ol

Yield: 77%.

HPLC-MS [M+H]⁺: 259.06; Rt=1.22 min (Method A).

Intermediate 382-Amino-6-((methyl(4-methylbenzyl)amino)methyl)pyrimidin-4-ol

Yield: 65%.

HPLC-MS [M+H]⁺: 259.10; Rt=1.20 min (Method A).

Intermediate 392-Amino-6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidin-4-ol

Yield: 90%.

¹H NMR (400 MHz, DMSO-d₆) δ: 10.66 (s, 1H), 7.10-7.02 (m, 4H), 6.50 (brs, 2H), 5.62 (s, 1H), 3.58 (s, 2H), 3.32 (s, 2H), 2.82 (m, 2H), 2.70 (m,2H).

Intermediate 40 2-Amino-6-(benzyloxymethyl)pyrimidin-4-ol

Yield: 71%.

¹H NMR (400 MHz, DMSO-d₆) δ: 10.68 (s, 1H), 7.39-6.97 (m, 5H), 6.51 (sbr, 2H), 5.60 (s, 1H), 4.55 (s, 2H), 4.15 (s, 2H).

Intermediate 413-((((2-Amino-6-hydroxypyrimidin-4-yl)methyl)(methyl)amino)methyl)benzonitrile

Yield: 99%.

HPLC-MS [M+H]⁺: 270.16; Rt=0.44 min (Method B).

Intermediate 422-Amino-6-(((4-ethylbenzyl)(methyl)amino)methyl)pyrimidin-4-ol

Yield: 99%.

HPLC-MS [M+H]⁺: 273.14; Rt=1.41 min (Method B).

Intermediate 432-Amino-6-(((4-fluorobenzyl)(methyl)amino)methyl)pyrimidin-4-ol

Yield: 64%.

HPLC-MS [M+H]⁺: 263.1; Rt=1.74 min (Method H).

Intermediate 44 2-Amino-6-((benzyl(ethyl)amino)methyl)pyrimidin-4-ol

Yield: 24%.

HPLC-MS [M+H]⁺: 259.21; Rt=1.92 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.62 (s, 1H), 7.35-7.30 (m, 4H), 7.24-7.23(m, 1H), 6.46 (br, s, 2H), 5.72 (s, 1H), 3.57 (s, 2H), 3.18 (s, 2H),2.51-2.42 (m, 2H), 1.02-0.98 (m, 3H).

Intermediate 452-Amino-6-((benzyl(2-methoxyethyl)amino)methyl)pyrimidin-4-ol

Yield: 63%.

HPLC-MS [M+H]⁺: 287.1; Rt=2.02 min (Method B).

Intermediate 462-Amino-6-((2-phenylpyrrolidin-1-yl)methyl)pyrimidin-4-ol

Yield: 28%.

HPLC-MS [M+H]⁺: 271.2; Rt=0.97 min (Method B).

Intermediate 472-Amino-6-(((3-methoxyphenyl)(methyl)amino)methyl)pyrimidin-4-ol

Yield: 77%.

HPLC-MS [M+H]⁺: 261.1; Rt=1.95 min (Method A).

General Procedure XI

Step 1:

Phosphoryl chloride (3 mL/mmol) was added to the appropriatepyrimidin-4-ol (1 eq) (ex:2-amino-6-((methyl(phenyl)amino)methyl)pyrimidin-4-ol) under nitrogenatmosphere. The reaction mixture was heated to 100° C. under stirringcondition for 1 h. The reaction mixture was cooled to room temperatureand evaporated under reduced pressure and co-distilled twice withtoluene to afford the desired crude product. The crude product was usedas such for the next step.

In same cases, the reaction was performed using phosphoryl chloride (10eq) as chlorinating agent.

Step 2:

To a stirred solution of the appropriate chloride (1 eq) (ex:4-chloro-6-((methyl(phenyl)amino)methyl)-pyrimidin-2-amine) in 1-butanol(13 mL/mmol) were added the corresponding aromatic amine (2 eq) (ex:p-toluidine) and sulphuric acid (catalytic, 2 drops) at roomtemperature. The reaction mixture was stirred at 100° C. for 16 h. Thereaction mixture was allowed to cool to room temperature and quenchedwith saturated sodium bicarbonate (pH-8). The aqueous layer wasextracted with ethyl acetate (2×), dried over anhydrous sodium sulphateand the solvent evaporated under reduced pressure. The resultant crudewas purified by flash column chromatography (dichloromethane/methanol)to obtain the desired product (ex:6-((methyl(phenyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine).

In same cases, isopropyl alcohol was used as solvent.

Example 286-((Benzyl(methyl)amino)methyl)-N⁴-o-tolylpyrimidine-2,4-diamine

Yield: 4.7% (over two steps).

HPLC-MS [M+H]⁺: 334.48; Rt=1.97 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.32 (s, 1H), 7.40-7.38 (d, J=7.2 Hz, 1H),7.32-7.18 (m, 7H), 7.11-7.09 (m, 1H), 6.07 (s, 1H), 5.95 (s, 2H), 3.47(s, 2H), 3.22 (s, 2H), 2.18 (s, 3H), 2.10 (s, 3H).

Example 293-(2-Amino-6-((benzyl(methyl)amino)methyl)pyrimidin-4-ylamino)benzonitrile

Yield: 13% (over two steps).

HPLC-MS [M+H]⁺: 345.22; Rt=1.60 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.45 (s, 1H), 8.37-8.36 (m, 1H), 7.90-7.87(m, 1H), 7.45 (t, J=8 Hz, 1H), 7.39-7.20 (m, 6H), 6.37 (br s, 2H), 6.30(s, 1H), 3.55 (s, 2H), 3.8 (s, 2H), 2.15 (s, 3H).

Example 306-((Benzyl(methyl)amino)methyl)-N⁴-(isoquinolin-7-yl)pyrimidine-2,4-diamine

Yield: 5% (over two steps).

HPLC-MS [M+H]⁺: 371.33; Rt=6.29 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.54 (s, 1H), 9.19 (s, 1H), 8.89 (s, 1H),8.33-8.32 (d, J=4 Hz, 1H), 7.84-7.83 (m, 2H), 7.70-7.68 (d, J=8 Hz, 1H),7.39-7.26 (m, 5H), 6.38-6.37 (d, J=4 Hz, 3H), 3.57 (s, 2H), 3.31 (s,2H), 2.17 (s, 3H).

Example 316-((Benzyl(methyl)amino)methyl)-N⁴-(isoquinolin-6-yl)pyrimidine-2,4-diamine

Yield: 4% (over two steps).

HPLC-MS [M+H]⁺: 371.21; Rt=1.24 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.61 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H),8.37-8.36 (d, J=4 Hz, 1H), 7.98-7.95 (d, J=12 Hz, 1H), 7.74-7.72 (d, J=8Hz, 1H), 7.66-7.65 (d, J=4 Hz, 1H), 7.40-7.26 (m, 5H), 6.41 (s, 3H),3.57 (s, 2H), 3.31 (s, 2H), 2.17 (s, 3H).

Example 326-((Methyl(3-methylbenzyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 5.4% (over two steps).

HPLC-MS [M+H]⁺: 348.25; Rt=1.78 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s br, 1H), 7.55 (d, J=8 Hz, 2H),7.24-7.20 (m, 1H), 7.15 (m, 2H), 7.07 (m, 3H), 6.23 (m, 3H), 3.50 (s,2H), 3.27 (s, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.14 (s, 3H).

Example 336-(((4-Methoxybenzyl)(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 7% (over two steps).

HPLC-MS [M+H]⁺: 364.26; Rt=1.61 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.25(d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.22(s, 1H), 6.09 (s, 2H), 3.74 (s, 3H), 3.45 (s, 2H), 3.22 (s, 2H), 2.25(s, 3H), 2.12 (s, 3H).

Example 346-((Methyl(4-methylbenzyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 16% (over two steps).

HPLC-MS [M+H]⁺: 348.29; Rt=1.80 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.56 (d, J=8.4 Hz, 2H), 7.22 (d, J=8 Hz,2H), 7.13 (d, J=7.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.23 (s, 1H), 6.08(s, 1H), 3.41 (s, 2H), 3.22 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.12(s, 3H).

Example 356-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 3.5% (over two steps).

HPLC-MS [M+H]⁺: 346.21; Rt=1.74 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.93 (s, 1H), 7.56 (d, J=8.4 Hz, 2H),7.11-7.03 (m, 6H), 6.18 (s, 2H), 6.13 (s, 2H), 3.60 (s, 2H), 3.40 (s,2H), 2.86-2.84 (m, 2H), 2.75-2.72 (m, 2H), 2.23 (s, 3H).

Intermediate 48 6-(Benzyloxymethyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 57% (over two steps).

HPLC-MS [M+H]⁺: 321.15; Rt=1.73 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 7.57 (d, J=8.4 Hz, 1H),7.38-7.37 (m, 4H), 7.33-7.31 (m, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.14 (s,3H), 4.57 (s, 2H), 4.25 (s, 2H), 2.24 (s, 3H).

Example 366-(((4-Methoxybenzyl)(methyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 36% (over two steps).

HPLC-MS [M+H]⁺: 380.33; Rt=1.63 min (Method G).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 7.44 (m, 1H), 7.27-7.25 (d,J=8.4 Hz, 2H), 7.20-7.12 (m, 2H), 6.90-6.88 (d, J=8.8 Hz, 2H), 6.51-6.49(m, 1H), 6.26 (s, 1H), 6.15 (br s, 2H), 3.74 (s, 6H), 3.46 (s, 2H), 3.23(s, 2H), 2.12 (s, 3H).

Example 373-((((2-Amino-6-(3-methoxyphenylamino)pyrimidin-4-yl)methyl)(methyl)amino)methyl)benzonitrile

Yield: 21.5% (over two steps).

HPLC-MS [M+H]⁺: 375.32; Rt=1.68 min (Method-A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.07 (s, 1H), 7.79 (s, 1H), 7.75-7.71 (m,2H), 7.58-7.55 (m, 1H), 7.44 (m, 1H), 7.22-7.20 (m, 1H), 7.16-7.12 (m,1H), 6.52-6.49 (m, 1H), 6.24 (s, 1H), 6.17 (br s, 2H), 3.74 (s, 3H),3.61 (s, 2H), 3.29 (s, 2H), 2.15 (s, 3H).

Example 38N⁴-β-Methoxyphenyl)-6-((methyl(3-methylbenzyl)amino)methyl)pyrimidine-2,4-diamine

Yield: 22% (over two steps).

HPLC-MS [M+H]⁺: 364.29; Rt=1.70 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 7.44 (m, 1H), 7.24-7.05 (m,6H), 6.52-6.49 (m, 1H), 6.27 (s, 1H), 6.15 (br s, 2H), 3.73 (s, 3H),3.49 (s, 2H), 3.25 (s, 2H), 2.30 (s, 3H), 2.13 (s, 3H).

Example 393-((((2-Amino-6-(m-tolylamino)pyrimidin-4-yl)methyl)(methyl)amino)methyl)benzonitrile

Yield: 21% (over two steps).

HPLC-MS [M+H]⁺: 359.20; Rt=1.72 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.99 (s, 1H), 7.78-7.70 (m, 3H), 7.58-7.53(m, 2H), 7.46 (s, 1H), 7.15-7.11 (t, J=5.0 Hz, 1H), 6.76-6.74 (d, J=7.6Hz, 1H), 6.24 (s, 1H), 6.15 (br s, 2H), 3.60 (s, 2H), 3.29 (s, 2H), 2.28(s, 3H), 2.15 (s, 3H).

Example 406-(((4-Ethylbenzyl)(methyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 43% (over two steps).

HPLC-MS [M+H]⁺: 378.32; Rt=1.83 (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 7.45-7.43 (m, 1H), 7.27-7.12(m, 6H), 6.52-6.49 (m, 1H), 6.27 (s, 1H), 6.15 (br s, 2H), 3.74 (s, 3H),3.49 (s, 2H), 3.24 (s, 2H), 2.61-2.52 (m, 2H), 2.14 (s, 3H), 1.19-1.15(t, J=7.6 Hz, 3H).

Example 416-((Benzyl(methyl)amino)methyl)-N⁴-(2,5-dimethoxyphenyl)pyrimidine-2,4-diamine

Yield: 16% (over two steps).

HPLC-MS [M+H]⁺: 380.29; Rt=1.61 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (s, 1H), 7.84-7.83 (d, J=4 Hz, 1H),7.36-7.25 (m, 5H), 6.92-6.90 (d, J=8 Hz, 1H), 6.55-6.52 (m, 1H), 6.42(s, 1H), 6.10 (br s, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 3.53 (s, 2H), 3.24(s, 2H), 2.13 (s, 3H).

Example 426-((Benzyl(methyl)amino)methyl)-N⁴-(2,3-dimethoxyphenyl)pyrimidine-2,4-diamine

Yield: 16% (over two steps).

HPLC-MS [M+H]⁺: 380.30; Rt=1.62 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (s, 1H), 7.79-7.77 (d, J=8 Hz, 1H),7.36-7.25 (m, 5H), 6.99-6.95 (t, J=8.4 Hz, 1H), 6.74-6.72 (m, 1H), 6.44(s, 1H), 6.08 (br s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.51 (s, 2H), 3.25(s, 2H), 2.13 (s, 3H).

Example 43N⁴-(Benzo[d][1,3]dioxol-4-yl)-6-((benzyl(methyl)amino)methyl)pyrimidine-2,4-diamine

Yield: 9% (over two steps).

HPLC-MS [M+H]⁺: 364.35; Rt=2.64 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.68 (s, 1H), 7.33-7.24 (m, 6H), 6.81-6.77(t, J=8.0 Hz, 1H), 6.69-6.67 (m, 1H), 6.26 (s, 1H), 6.05 (br s, 2H),5.97 (s, 2H), 3.51 (s, 2H), 3.24 (s, 2H), 2.12 (s, 3H).

Example 44N⁴-(Benzo[d][1,3]dioxol-4-yl)-6-((benzyl(methyl)amino)methyl)pyrimidine-2,4-diamine

Yield: 17% (over two steps).

HPLC-MS [M+H]⁺: 364.3; Rt=1.58 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H), 7.53 (s, 1H), 7.36-7.25 (m,5H), 6.96-6.94 (d, J=8 Hz, 1H), 6.82-6.80 (d, J=8 Hz, 1H), 6.20 (s, 1H),6.12 (br, s, 2H), 5.96 (s, 2H), 3.52 (s, 2H), 3.24 (s, 2H), 2.14 (s,3H).

Example 456-(((4-Fluorobenzyl)(methyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 25% (over two steps).

HPLC-MS [M+H]⁺: 368.32; Rt=1.67 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 7.45-7.37 (m, 3H), 7.20-7.13(m, 4H), 6.51-6.49 (m, 1H), 6.25 (s, 1H), 6.16 (br, s, 2H), 3.74 (s,3H), 3.52 (s, 2H), 3.26 (s, 2H), 2.13 (s, 3H).

Example 466-((Benzyl(methyl)amino)methyl)-N⁴-(2-methoxy-5-methylphenyl)pyrimidine-2,4-diamine

Yield: 49% (over two steps).

HPLC-MS [M+H]⁺: 364.33; Rt=1.74 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m,5H), 6.90-6.88 (m, 1H), 6.84-6.81 (m, 1H), 6.30 (s, 1H), 6.04 (br s,2H), 3.75 (s, 3H), 3.51 (s, 2H), 3.23 (s, 2H), 2.25 (s, 3H), 2.12 (s,3H).

Example 476-(((4-Methoxybenzyl)(methyl)amino)methyl)-N⁴-m-tolylpyrimidine-2,4-diamine

Yield: 15% (over two steps).

HPLC-MS [M+H]⁺: 364.38; Rt=2.83 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.98 (s, 1H), 7.55-7.53 (d, J=8.0 Hz, 1H),7.47 (s, 1H), 7.27-7.25 (d, J=8.0 Hz, 2H), 7.15-7.11 (t, J=8.0 Hz, 1H),6.90-6.88 (d, J=8.0 Hz, 2H), 6.76-6.74 (d, J=8.0 Hz, 1H), 6.25 (s, 1H),6.13 (br, s, 2H), 3.74 (s, 3H), 3.46 (s, 2H), 3.23 (s, 2H), 2.28 (s,3H), 2.12 (s, 3H).

Example 486-((Benzyl(ethyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 21% (over two steps).

HPLC-MS [M+H]⁺: 364.3; Rt=1.71 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 7.44-7.43 (t, J=4.4 Hz, 1H),7.38-7.30 (m, 4H), 7.25-7.21 (m, 2H), 7.16-7.12 (t, J=8.0 Hz, 1H),6.51-6.49 (m, 1H), 6.32 (s, 1H), 6.13 (br, s, 2H), 3.74 (s, 3H), 3.58(s, 2H), 3.29 (s, 2H), 2.47-2.45 (m, 2H), 1.04-1.00 (t, J=14 Hz, 3H).

Example 496-((Benzyl(2-methoxyethyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 39% (over two steps).

HPLC-MS [M+H]⁺: 394.36; Rt=1.80 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.07 (s, 1H), 7.43-7.42 (t, J=4.4 Hz, 1H),7.38-7.30 (m, 4H), 7.26-7.21 (m, 2H), 7.16-7.12 (t, J=8.0 Hz, 1H),6.52-6.49 (m, 1H), 6.31 (s, 1H), 6.14 (br, s, 2H), 3.74 (s, 3H), 3.64(s, 2H), 3.46-3.43 (t, J=12.4 Hz, 2H), 3.36 (s, 2H), 3.19 (s, 3H),2.16-2.58 (t, J=2.0 Hz, 2H).

Example 50N⁴-β-Methoxyphenyl)-6-((2-phenylpyrrolidin-1-yl)methyl)pyrimidine-2,4-diamine

Yield: 15% (over two steps).

HPLC-MS [M+H]⁺: 376.41; Rt=3.02 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 7.47-7.46 (t, J=4.4 Hz, 1H),7.42-7.40 (d, J=6.8 Hz, 2H), 7.35-7.31 (t, J=7.0 Hz, 2H), 7.25-7.21 (t,J=8.0 Hz, 2H), 7.16-7.11 (t, J=8.0 Hz, 1H), 6.51-6.48 (m, 1H), 6.22 (s,1H), 6.12 (br s, 2H), 3.74 (s, 3H), 3.47-3.41 (m, 2H), 3.27-3.23 (m,1H), 2.89-2.85 (d, J=15.2 Hz, 1H), 2.25-2.15 (m, 2H), 1.83-1.80 (m, 2H),1.60-1.55 (m, 1H).

Example 51N⁴-β-Methoxyphenyl)-6-(((3-methoxyphenyl)(methyl)amino)methyl)pyrimidine-2,4-diamine

Yield: 6% (over two steps).

HPLC-MS [M+H]⁺: 366.38; Rt=3.08 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 7.40-7.39 (t, J=4 Hz, 1H),7.17-7.15 (d, J=8 Hz, 1H), 7.11-7.02 (m, 2H), 6.48-6.46 (dd, J=8 Hz,1H), 6.25-6.20 (m, 4H), 6.15-6.14 (t, J=4 Hz, 1H), 5.78 (s, 1H), 4.21(s, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.05 (s, 3H).

Example 526-((Benzyl(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

To a stirred solution of compound4-((benzyl(methyl)amino)methyl)-6-chloropyrimidin-2-amine (120 mg, 0.4mmol, 1.0 eq) in tetrahydrofurane (5 mL) was addedN,N-diisopropylethylamine (0.385 mL, 2.28 mmol, 5 eq) at roomtemperature and it was stirred for 20 min. To the reaction mixture, wasadded p-toluidine (0.068 g, 6.35 mmol, 1.5 eq) and the mixture wasstirred for 16 h at room temperature and further stirred for 4 h at 70°C. After completion of the reaction, reaction mixture was poured intocold water and extracted with ethyl acetate. Organic extracts were driedover anhydrous sodium sulfate and solvent was evaporated under reducedpressure to get crude compound. The crude was purified by preparativereverse phase prep HPLC to get the product6-((benzyl(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine as paleyellow solid.

Yield: 4% (over two steps).

HPLC-MS [M+H]⁺: 334.3; Rt=1.63 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (br s, 1H), 7.57-7.55 (d, J=8.4 Hz,2H), 7.36-7.31 (m, 4H), 7.28-7.26 (m, 1H), 7.07-7.05 (d, J=8.0 Hz, 2H),6.24 (s, 1H), 6.10 (br s, 2H), 3.53 (s, 2H), 3.25 (s, 2H), 2.25 (s, 3H),2.15 (s, 3H).

Intermediate 49 Tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-formylpyrimidin-2-yl)carbamate

Step 1:

Boc anhydride (43 ml, 188.4 mmol, 6 eq) was added to a stirred solutionof 6-(benzyloxymethyl)-N⁴-p-tolylpyrimidine-2,4-diamine (Intermediate48) (10 g, 31.4 mmol, 1 eq) and dimethylaminopyridine (0.383 g, 3.14mmol, 0.1 eq) in tetrahydrofurane at 0° C., then the reaction mixturewas heated at 90° C. for 6 h. The reaction mixture was diluted withwater and extracted with ethyl acetate (3×25 mL). The combined organicextracts were washed with water and brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure to getthe crude product which was purified by flash column chromatography(2-4% methanol/dichloromethane) to get 14 g of product tert-butyl(4-((benzyloxy)methyl)-6-((tert-butoxycarbonyl)(p-tolyl)amino)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate(yield: 72%).

HPLC-MS [M+H]⁺: 621.55; Rt=1.61 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.83 (s, 1H), 7.39-7.38 (m, 1H), 7.19 (d,J=8 Hz, 2H), 7.05 (d, J=8 Hz, 2H), 4.65 (s, 2H), 4.60 (s, 2H), 2.31 (s,3H), 1.44-1.39 (m, 27H).

Step 2:

10% Palladium on Charcoal (5 g) was added under nitrogen to a stirredsolution of compound tert-butyl(4-((benzyloxy)methyl)-6-((tert-butoxycarbonyl)(p-tolyl)amino)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate(16 g, 25.5 mmol, 1 eq) in methanol (100 ml) at room temperature. Thereaction mixture was stirred at same temperature under hydrogen pressurefor 16 h. The reaction mixture was filtered through celite bed, washedwith methanol and evaporated under reduced pressure to afford 12.4 g ofpure product tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)carbamate(yield: 92%).

HPLC-MS [M+H]⁺: 531.61; Rt=2.46 min (Method A).

Step 3:

Dess-Martin periodinane was slowly added to a solution of compoundtert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)carbamatein dichloromethane at 0° C. Then reaction mixture was warmed to roomtemperature and stirred for 3 h. The reaction mixture was quenched withsaturated solution of sodium thiosulphate and sodium bicarbonate andorganic product was extracted with dichloromethane. Combined organicswere dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure to get crude product. The crude product was purified byflash column chromatography (2-3% methanol/dichloromethane) to afford 8g of compound tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-formylpyrimidin-2-yl)carbamate(yield: 73%).

HPLC-MS [M+H]⁺: 529.44; Rt=2.67 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.91 (s, 1H), 8.24 (s, 1H), 7.21 (d, J=8Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 2.32 (s, 3H), 1.38-1.29 (m, 27H).

General Procedure XII

Step 1:

Catalytic acetic acid was added to a stirred solution of the appropriateformyl pyrimidine (1 eq) (ex: tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-formylpyrimidin-2-yl)carbamate)and the appropriate benzyl amine (1.5 eq) (ex:1-(3-methoxyphenyl)-N-methylmethanamine) in 1,2-dichloroethane at 0° C.then followed by sodium cyanoborohydride (2 eq) was added then thereaction mixture was stirred at room temperature for 16 h. Aftercompletion of the reaction, the reaction mixture was quenched withminimum amount of saturated sodium bicarbonate solution, the organicproduct was extracted with dichloromethane (3×). The combined organicextracts were dried over anhydrous sodium sulfate. Solvent was distilledunder reduced pressure to give the crude compound. The crude waspurified by flash column chromatography (10-20% ethyl acetate/petroleumether or 2-5% methanol/dichloromethane) to get the desired BOC protectedproduct (ex: tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-(((3-methoxybenzyl)(methyl)amino)methyl)pyrimidin-2-yl)carbamate).

In some examples, the reaction was carried out with trimethylorthoformate (10 eq) and sodium triacetoxyborohydride (2.5 eq).

Step 2:

To a stirred dioxane solution of the BOC-protected compound (ex:tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(p-tolyl)amino)-6-(((3-methoxybenzyl)(methyl)-amino)methyl)pyrimidin-2-yl)carbamate)at 0° C. was added 4M HCl and the mixture was stirred at roomtemperature for 48 h. The reaction mixture was further heated at 50° C.for 2 h. The reaction mixture was evaporated under reduced pressure toget crude which was quenched with minimum amount of aqueous sodiumbicarbonate solution. The organic product was extracted withdichloromethane (3×). The combined organic extracts were dried overanhydrous sodium sulfate. Solvent was distilled under reduced pressureto give the crude compound The crude was purified by flash columnchromatography (neutral alumina, 15% methanol/dichloromethane) andfurther purified by reverse phase preparative HPLC to get the finaldesired de-protected product (ex:6-(((3-methoxybenzyl)(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine).

In same cases, trifluoroacetic acid was used instead HCl and withdichloromethane as solvent.

Example 536-(((3-Methoxybenzyl)(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 10%.

HPLC-MS [M+H]⁺: 364.24; Rt=1.69 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H), 7.55 (d, J=8.4 Hz, 2H),7.26-7.22 (m, 1H), 6.93-6.91 (d, J=7.6 Hz 2H), 6.83-6.81 (m, 1H), 6.24(s, 1H), 6.09 (s, 2H), 3.73 (s, 3H), 3.51 (s, 2H), 3.24 (s, 2H), 2.24(s, 3H), 2.15 (s, 3H).

Example 546-(((3-Chlorobenzyl)(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Yield: 36%.

HPLC-MS [M+H]⁺: 368.23; Rt=1.80 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (s, 1H), 7.55 (d, J=8.4 Hz, 2H),7.40-7.30 (m, 4H), 7.06 (d, J=8 Hz, 2H), 6.22 (s, 1H), 6.10 (br s, 2H),3.55 (s, 2H), 3.26 (s, 2H), 2.24 (s, 3H), 2.14 (s, 3H).

Example 553-((((2-Amino-6-(p-tolylamino)pyrimidin-4-yl)methyl)(methyl)amino)methyl)benzonitrile

Yield: 21%.

HPLC-MS [M+H]⁺: 359.21; Rt=1.77 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (s, 1H), 7.78-7.69 (m, 3H), 7.58-7.54(m, 3H), 7.06 (d, J=8 Hz, 2H), 6.21 (s, 1H), 6.11 (br s, 1H), 3.60 (s,2H), 3.28 (s, 2H), 2.24 (s, 3H), 2.14 (s, 3H).

Example 566-(((4-Chlorobenzyl)(methyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Trifluoroacetic acid and dichloromethane were used in the second step.

Yield: 42%.

HPLC-MS [M+H]⁺: 368.21; Rt=1.85 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.38(m, 4H), 7.06 (d, J=8.4 Hz, 2H), 6.21 (s, 1H), 6.10 (br s, 2H), 3.52 (s,2H), 3.23 (s, 2H), 2.25 (s, 3H), 2.14 (s, 3H).

Example 574-((((2-Amino-6-(p-tolylamino)pyrimidin-4-yl)methyl)(methyl)amino)methyl)benzonitrile

Trifluoroacetic acid and dichloromethane were used.

Yield: 23%.

HPLC-MS [M+H]⁺: 359.28; Rt=1.76 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (s, 1H), 7.81 (d, J=8 Hz, 2H),7.57-7.55 (m, 4H), 7.06 (d, J=8 Hz, 2H), 6.21 (s, 1H), 6.11 (s, 2H),3.63 (s, 2H), 3.27 (s, 2H), 2.25 (s, 3H), 2.16 (s, 3H).

Example 586-((Methyl(1,2,3,4-tetrahydronaphthalen-2-yl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine

Yield: 44%.

HPLC-MS [M+H]⁺: 374; Rt=2.13 min (Method A).

¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.3 Hz,2H), 7.04-6.96 (m, 4H), 6.47 (s, 1H), 6.23 (s, 1H), 4.89 (s, 2H), 3.44(s, 2H), 2.94-2.65 (m, 5H), 2.28 (s, 6H), 2.03-1.97 (m, 1H), 1.70-1.64(m, 1H).

Example 596-(((2-(2-(2-Aminoethoxy)ethoxy)ethyl)(benzyl)amino)methyl)-N⁴-(p-tolyl)pyrimidine-2,4-diamine

Yield: 30%.

HPLC-MS [M+H]⁺: 451; Rt=1.75 min (Method A).

¹H NMR (400 MHz, CD₃OD) δ 7.40 (d, J=8.3 Hz, 2H), 7.34 (d, J=6.9 Hz,2H), 7.29 (d, J=7.0 Hz, 2H), 7.22 (t, J=7.1 Hz, 1H), 7.13 (d, J=8.2 Hz,2H), 6.38 (s, 1H), 3.67 (s, 2H), 3.59-3.57 (m, 4H), 3.54-3.52 (m, 2H),3.46 (s, 2H), 3.30 (dt, J=3.3, 1.6 Hz, 2H), 2.99-2.92 (m, 2H), 2.69 (t,J=5.8 Hz, 2H), 2.31 (s, 3H).

Example 606-((Methyl(pyridin-4-ylmethyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Trifluoroacetic acid and dichloromethane were used in the second step.

Yield: 5%.

HPLC-MS [M+H]⁺: 335.23; Rt=1.39 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.96 (s, 1H), 8.53-8.52 (m, 2H), 7.57-7.55(d, J=8.4 Hz, 2H). 7.38-7.36 (m, 2H), 7.07-7.05 (d, J=8.4 Hz, 2H), 6.23(s, 1H), 6.11 (s, 2H), 3.58 (s, 2H), 3.31 (s, 2H), 2.25 (s, 3H), 2.17(s, 3H).

Example 616-((Methyl(pyridin-3-ylmethyl)amino)methyl)-N⁴-p-tolylpyrimidine-2,4-diamine

Trifluoroacetic acid and dichloromethane were used in the second step

Yield: 38%.

HPLC-MS [M+H]⁺: 335.25 Rt=1.37 min (Method-A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.57 (s, 1H), 8.49-8.47 (m,1H), 7.75-7.73 (d, J=8 Hz, 1H). 7.58-7.56 (d, J=8 Hz, 2H), 7.38-7.35 (m,1H), 7.07-7.05 (d, J=8.4 Hz, 2H), 6.23 (s, 1H), 6.11 (br s, 2H), 3.57(s, 2H), 3.27 (s, 2H), 2.24 (s, 3H), 2.15 (s, 3H).

Example 62N-((2-Amino-6-(3-methoxyphenylamino)pyrimidin-4-yl)methyl)-N-methylbenzamide

Step 1:

Boc anhydride (1.7 mL, 7.9 mmol, 6 eq) was added to a stirred solutionof6-(((4-methoxybenzyl)(methyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-2,4-diamine(0.5 g, 1.3 mmol, 1 eq) and dimethylaminopyridine (0.016 g, 0.13 mmol,0.1 eq) in tetrahydrofuran at 0° C. and the reaction mixture heated to100° C. for 6 h. The reaction mixture was diluted with water, extractedwith ethyl acetate (3×10 mL). The combined organic extracts were washedwith water, brine, dried over anhydrous sodium sulfate and solvent wasevaporated under reduced pressure to get crude product. The crudeproduct was purified by flash column chromatography (15-20% ethylacetate/petroleum ether) to get 0.75 g of product tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-(((4-methoxybenzyl)(methyl)amino)methyl)pyrimidin-2-yl)carbamate(yield: 83.7%). HPLC-MS [M+H]⁺: 364.33; Rt=3.71 min (Method H).

Step 2:

10% Pd/C (0.4 g) was added to a stirred solution of compound tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-(((4-methoxybenzyl)(methyl)amino)methyl)pyrimidin-2-yl)carbamate(0.75 g, 1.1 mmol, 1 eq) in methanol (20 mL) under nitrogen at roomtemperature. The reaction mixture was stirred at same temperature underhydrogen pressure for 16 h. The reaction mixture was filtered throughcelite bed, washed with methanol and filtrate was evaporated underreduced pressure to afford 0.35 g of crude product tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-((methylamino)methyl)pyrimidin-2-yl)carbamatewhich was used for next step as such without any purification.

ES-MS [M+H]⁺: 560.3; Rt=2.68 min (Method H).

Step 3:

HATU (0.24 g, 0.64 mmol, 1.2 eq) was added portion wise to a solution ofN,N-diisopropylethylamine (0.18 mL, 1.0 mmol, 2 eq) and compoundtert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-((methylamino)methyl)pyrimidin-2-yl)carbamate(0.3 g, 0.53 mmol, 1 eq) in dimethyl formamide (3 mL) at 0° C. Thereaction mixture was stirred for 10 minutes at same temperature. To thereaction mixture was added benzoic acid (0.078 g, 0.64 mmol, 1.2 eq) at0° C. and the reaction mixture was stirred at room temperature for 16 h.The reaction mixture was quenched with minimum amount of saturatedsodium bicarbonate solution, the organic product was extracted withethyl acetate (2×10 mL). The combined organic extracts were dried overanhydrous sodium sulfate. Solvent was distilled under reduced pressureto give the crude compound. The crude product was purified by flashcolumn chromatography (20-30% ethyl acetate/petroleum ether) to get 0.25g of product tert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-((N-methylbenzamido)methyl)pyrimidin-2-yl)carbamate(yield: 70%).

HPLC-MS [M+H]⁺: 664.3; Rt=3.17 min (Method H).

Step 4:

Trifluoroacetic acid (3 mL) was added to a stirred solution of compoundtert-butyl(tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)β-methoxyphenyl)amino)-6-((N-methylbenzamido)methyl)pyrimidin-2-yl)carbamate(0.25 g, 0.37 mmol, 1 eq) in dichloromethane (5 mL) 0° C. and then thereaction mixture was stirred at room temperature for 3 h. The reactionmixture was evaporated under reduced pressure to obtain crude. The crudeproduct was purified by reverse phase prep HPLC to afford 70 mg of purecompoundN-((2-amino-6-(3-methoxyphenylamino)pyrimidin-4-yl)methyl)-N-methylbenzamide(yield: 51%).

HPLC-MS [M+H]⁺: 364.33; Rt=1.60 min (Method E).

¹H NMR (400 MHz, VT, DMSO-d₆) δ: 8.86 (s, 1H), 7.42-7.34 (m, 6H),7.18-7.12 (m, 2H), 6.55-6.52 (m, 1H), 5.99 (s, 1H), 5.92 (br, s, 2H),4.26 (br, s, 2H), 3.75 (s, 3H), 2.69 (s, 3H).

General Procedure XIII

To a stirred solution of the dichloro compound (ex:N-benzyl-1-(4,6-dichloropyrimidin-2-yl)-N-methylmethanamine;Intermediate 21) (1 eq) in 1-butanol (13 mL/mmol) were added thecorresponding aniline (ex. 2-methoxyaniline) (0.7 eq), sulfuric acid(catalytic, 2 drops) at room temperature and heated to 100° C. for 16 h.After completion of the reaction, the reaction mixture was allowed tocool to room temperature and diluted with water and basified withsaturated sodium bicarbonate (pH-8). The aqueous layer was extractedtwice with ethyl acetate, dried over anhydrous sodium sulfate andsolvent was evaporated under reduced pressure to get crude compound. Thecrude was purified by flash column chromatography (2-15%methanol/dichloromethane or 10-60% ethyl acetate/heptanes) to get theproduct (ex:2-((benzyl(methyl)amino)methyl)-6-chloro-N-(2-methoxyphenyl)pyrimidin-4-amine).

In same examples, the reaction was carried using concentratedhydrochloric acid and sodium iodide (1 eq) and water as solvent.

Intermediate 502-((Benzyl(methyl)amino)methyl)-6-chloro-N-(2-methoxyphenyl)pyrimidin-4-amine

Yield: 43%.

HPLC-MS [M+H]⁺: 369.18; Rt=1.76 min (Method B).

Intermediate 512-((Benzyl(methyl)amino)methyl)-6-chloro-N-m-tolylpyrimidin-4-amine

Yield: 37%.

HPLC-MS [M+H]⁺: 353.38; Rt=2.80 min (Method A).

Intermediate 522-((Benzyl(methyl)amino)methyl)-6-chloro-N-(3-methoxyphenyl)pyrimidin-4-amine

Yield: 31%.

HPLC-MS [M+H]⁺: 369.27; Rt=1.77 min (Method B).

Intermediate 532-((Benzyl(methyl)amino)methyl)-6-chloro-N-(4-methoxyphenyl)pyrimidin-4-amine

Yield: 33%.

HPLC-MS [M+H]⁺: 369.18; Rt=1.76 min (Method B).

General Procedure XIV

Step 1:

To a stirred and degassed solution of the chloro pyrimidine intermediate(ex:2-((benzyl(methyl)amino)methyl)-6-chloro-N-(2-methoxyphenyl)pyrimidin-4-amine;Intermediate 50) (1.0 eq), tert-butyl carbamate (2.0 eq) in 1,4-dioxane(6 mL) were added cesium carbonate (3.0 eq) XPhos (0.05 eq), Pd₂(dba)₃(0.1 eq) and heated to 90° C. for 16 h. After completion of thereaction, the reaction mixture was allowed to cool to room temperatureand diluted with water and the organic product was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andsolvent was evaporated under reduced pressure. The crude was purified byflash column chromatography (20/60% ethyl acetate/petroleum ether) toget the Boc-protected amine product (ex: tert-butyl(2-((benzyl(methyl)amino)methyl)-6-(p-tolylamino)pyrimidin-4-yl)carbamate).

Step 2:

A solution of the BOC-protected compound (ex: tert-butyl 2-((benzyl(methyl) amino) methyl)-6-(p-tolylamino) pyrimidin-4-ylcarbamate) (1 eq)in 4N hydrochloric acid in 1,4-dioxane (10 eq) was stirred at roomtemperature for 16 h. After completion of the reaction, the reactionmixture was evaporated under reduced pressure. The crude was basifiedwith saturated sodium bicarbonate and the product was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and evaporated. The crude was purified by preparative HPLC(reverse phase) to get the amine product (ex:2-((benzyl(methyl)amino)methyl)-N⁴-(2-methoxyphenyl)pyrimidine-4,6-diamine;Example 63)

Example 632-((Benzyl(methyl)amino)methyl)-N⁴-(2-methoxyphenyl)pyrimidine-4,6-diamine

Yield: 21% (over two steps).

HPLC-MS [M+H]⁺: 350.23; Rt=1.67 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.86-7.81 (m, 2H), 7.35-7.22 (m, 5H), 7.02(d, J=4.4 Hz, 2H), 6.90-6.89 (m, 1H), 6.23 (s, 2H), 5.62 (s, 1H), 3.80(s, 3H), 3.62 (s, 2H), 3.36 (s, 2H), 2.18 (s, 3H).

Example 642-((Benzyl(methyl)amino)methyl)-N⁴-m-tolylpyrimidine-4,6-diamine

Trifluoroacetic acid and dichloromethane were used.

Yield: 5% (over two steps).

HPLC-MS [M+H]⁺: 334.1; Rt=2.09 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.77 (s, 1H), 7.39-7.23 (m, 7H), 7.12 (t,J=7.6 Hz, 1H), 6.73 (d, J=4.0 Hz 1H), 6.27 (s, 2H), 5.68 (s, 1H), 3.64(s, 2H), 3.39 (s, 2H), 2.25 (s, 3H), 2.20 (s, 3H).

Example 652-((Benzyl(methyl)amino)methyl)-N⁴-(3-methoxyphenyl)pyrimidine-4,6-diamine

Trifluoroacetic acid and dichloromethane were used.

Yield: 4% (over two steps).

HPLC-MS [M+H]⁺: 350.29; Rt=1.91 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 7.38-7.23 (m, 6H), 7.15-7.05(m, 2H), 6.49-6.47 (m, 1H), 6.31 (s, 2H), 5.70 (s, 1H), 3.71 (s, 3H),3.62 (s, 2H), 3.39 (s, 2H), 2.19 (s, 3H).

Example 662-((Benzyl(methyl)amino)methyl)-N⁴-(4-methoxyphenyl)pyrimidine-4,6-diamine

Trifluoroacetic acid and dichloromethane were used.

Yield: 6% (over two steps).

HPLC-MS [M+H]⁺: 350.29; Rt=1.84 min (Method A).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.60 (s, 1H), 7.40-7.23 (m, 7H), 6.86-6.84(d, J=8.0 Hz, 2H), 6.20 (s, 2H), 5.55 (s, 1H), 3.73 (s, 3H), 3.62 (s,2H), 3.36 (s, 2H), 2.19 (s, 3H).

Intermediate 546-((Benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine

Step 1:

To a stirred solution of compound methyl2-chloro-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylate(0.5 g, 1.67 mmol, 1 eq), N-methylbenzylamine (0.202 g, 1.67 mmol, 1.0eq) in tetrahydrofuran (10 mL) at room temperature was added1,5,7-triazabicyclo[4.4.0]dec-5-ene (69.6 mg, 0.5 mmol, 0.3 eq) andstirred for 3 h at room temperature. After completion of the reaction,the reaction mixture was diluted with water and the organic product wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by flash columnchromatography (10-50% ethyl acetate/petroleum ether) to get compoundN-benzyl-2-chloro-N-methyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide(0.21 g, yield: 32%) as a pale yellow thick liquid.

HPLC-MS [M+H]⁺: 289.3; Rt=2.281 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.74-7.73 (d, J=6.4 Hz, 1H), 7.40-7.25 (m,5H), 6.55 (s, 1H), 4.61 (s, 1H), 4.50 (s, 1H), 2.83-2.82 (m, 3H), 3.37(s, 2H), 1.88-1.86 (m, 2H), 1.42-1.41 (m, 6H), 0.92-0.88 (m, 9H).

Step 2:

To a stirred solution of compoundN-benzyl-2-chloro-N-methyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide(0.21 g, 0.5 mmol, 1 eq) in tetrahydrofuran at 0° C. was added boranedimethyl sulfide complex (0.16 mL, 1.5 mmol, 3 eq) and stirred at 70° C.for 4 h. The reaction mixture was allowed to cool to 0° C., quenchedwith 2N hydrochloric acid, basified with saturated sodium bicarbonatesolution (pH-8) and the organic product was extracted intodichloromethane. The organic layer was dried over anhydrous sodiumsulfate and solvent was evaporated under reduced pressure to get crudeproduct. The crude product was purified by flash column chromatography(10-50% ethyl acetate/petroleum ether) to get compound6-((benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine(80 mg, yield: 39%) as thick liquid.

HPLC-MS [M+H]⁺: 375.3; Rt=1.90 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.66 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.37-7.11 (m, 10H), 3.64 (s, 2H), 3.37 (s, 2H), 2.22 (s, 3H).

General Procedure XV

Step 1:

To a stirred solution of compound6-((benzyl(methyl)amino)methyl)-2-chloro-N-(2,4,4-trimethylpentan-2-yl)pyrimidin-4-amine(1 eq) in 1-butanol (13 mL/mmol) at room temperature were added theappropriate amine (ex: p-toluidine) (0.04 g, 0.4 mmol, 2.0 eq),catalytic sulfuric acid (2 drops) and heated to 110° C. for 16 h. Aftercompletion of the reaction, the reaction mixture was cooled to roomtemperature and slowly basified with saturated sodium bicarbonate andthe organic product was extracted into ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and solvent was evaporated underreduced pressure to get crude product. The crude product was purified byflash column chromatography (10-60% ethyl acetate/petroleum ether or2-8% methanol/dichloromethane) to get the desired compound (ex:6-((benzyl(methyl)amino)methyl)-N²-p-tolyl-N-(2,4,4-trimethylpentan-2-yl)pyrimidine-2,4-diamine).

Step 2:

To a stirred solution of the appropriate protected compound (ex:6-((benzyl(methyl)amino)methyl)-N²-p-tolyl-N⁴-(2,4,4-trimethylpentan-2-yl)pyrimidine-2,4-diamine)in dichloromethane (3 mL) at room temperature was added trifluoro aceticacid (7 eq) and heated to 40° C. for 16 h. The reaction mixture wasevaporated completely to get the residue which was basified withsaturated sodium bicarbonate and the organic product was extracted intodichloromethane. The organic layer was dried over anhydrous sodiumsulfate and solvent was evaporated under reduced pressure. The crudeproduct was purified by flash column chromatography (20-60% ethylacetate/petroleum ether or 2-8% methanol/dichloromethane) to get thedesired free amine compound (ex:6-((benzyl(methyl)amino)methyl)-N²-p-tolylpyrimidine-2,4-diamine;Example 23; yield 13% over two steps).

Example 67 6-((Benzyl(methyl)amino)methyl)-N²-(2-methoxyphenyl)pyrimidine-2, 4-diamine

Yield: 14% (over two steps).

HPLC-MS [M+H]⁺: 350.44; Rt=1.95 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.52-8.49 (m, 1H), 7.39-7.32 (m 4H),7.27-7.26 (m, 2H), 6.99-6.96 (m, 1H), 6.89-6.87 (m, 2H), 6.64 (br s.2H), 6.17 (s, 1H), 3.86 (s, 3H), 3.56 (s, 2H), 3.28 (s, 2H), 2.16 (s,3H).

Example 686-((Benzyl(methyl)amino)methyl)-N²-m-tolylpyrimidine-2,4-diamine

Yield: 11% (over two steps).

HPLC-MS [M+H]⁺: 334.24; Rt=1.64 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.77 (s, 1H), 7.66-7.64 (d, J=8 Hz, 1H),7.56 (s, 1H), 7.38-7.32 (m, 4H), 7.28-7.26 (m, 1H), 7.08-7.04 (t, J=8Hz, 1H), 6.66-6.64 (d, J=8 Hz, 1H), 6.50 (br s, 2H), 6.13 (s, 1H), 3.55(s, 2H), 3.32-3.31 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H).

Example 696-((Benzyl(methyl)amino)methyl)-N²-(3-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 30% (over two steps).

HPLC-MS [M+H]⁺: 350.74; Rt=1.91 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 7.62-7.61 (m, 3H), 7.38-7.26(m, 6H), 7.09-7.05 (t, J=8.0, 1H), 6.52 (br s, 2H), 6.43-6.40 (dd,J=8.2, 1.8 Hz, 1H), 6.15 (s, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 3.31 (s,2H), 2.16 (s, 3H).

Example 70 6-((Benzyl(methyl)amino methyl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine

Yield: 7% (over two steps).

HPLC-MS [M+H]⁺: 350.28; Rt=1.54 min (Method E).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H), 7.68-7.66 (d, J=6.8 Hz, 2H),7.38-7.32 (m, 4H), 7.27-7.26 (m, 1H), 6.79-6.77 (d, J=8 Hz, 2H), 6.44(br s, 2H), 6.10 (s, 1H), 3.69 (s, 3H), 3.55 (s, 2H), 3.28 (s, 2H), 2.15(s, 3H).

Example 71(6-((3,4-Dihydroisoquinolin-2(1H)-yl)methyl)-N-(2-methoxyphenyl)pyrimidine-2,4-diamine)

Step 1:

(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidine-2,4(1H,3H)-dione)1,2,3,4-tetrahydroisoquinoline (3.4 g, 25.7 mmol, 1.2 eq) was added to astirred solution of2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbaldehyde (3 g, 21.4 mmol, 1eq) and acetic acid (cat.) in 1,2-dichloroethane-methanol (25:25 mL) at0° C. and stirred at room temperature for 2 h. The reaction mixture wascooled to 0° C. and NaCNBH₃ (2.7 g, 42.8 mmol, 2 eq) was added andfurther allowed to come to room temperature and stirred for 16 h. Aftercompletion of the reaction, the reaction mixture was evaporated underreduced pressure then quenched with minimum amount of saturated sodiumbicarbonate solution and extracted with dichloromethane (3×100 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate.Solvent was distilled under reduced pressure to give the crude compound.The crude product purified by flash column chromatography (10-20%methanol/dichloromethane) as eluent to afford 0.8 g pure compound(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidine-2,4(1H,3H)-dioneas yellow solid (yield: 14.5%).

HPLC-MS [M+H]⁺: 258.2; Rt=2.17 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.95 (s, 1H), 10.71 (s, 1H), 7.11-7.03 (m,4H), 5.50 (s, 1H), 3.61 (s, 2H), 3.35 (s, 2H), 2.84-2.81 (t, J=4 Hz,2H), 2.73-2.70 (t, J=4 Hz, 4H).

Step 2:

Phosphoryl chloride (10 mL) was added to(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidine-2,4(1H,3H)-dione(0.8 g, 3.1 mmol, 1 eq) at room temperature under nitrogen atmosphereand then heated to 120° C. for 16 h. The reaction mixture was evaporatedunder reduced pressure to get the crude product. The crude was quenchedwith ice water and then basified (up to pH-8) using 10% sodiumbicarbonate solution. The organic product was extracted withdichloromethane (2×20 mL). The organic layer was washed with water,brine, dried over anhydrous sodium sulfate and solvent was concentratedunder reduced pressure to afford 0.5 g of crude product2-((2,6-dichloropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline.

HPLC-MS [M+H]⁺: 294.00; Rt=1.95 min (Method C).

Step 3:

Ammonia gas was purged to compound2-((2,6-dichloropyrimidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline(0.4 g, 1.36 mmol, 1 eq) at −78° C. in sealed tube and stirred at roomtemperature for 4 h. The reaction mixture was then cooled and solventwas concentrated under reduced pressure to afford 0.2 g of crude product2-chloro-6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidin-4-amine.

ES-MS [M+H]⁺: 275.1; Rt=2.31 min (Method A).

Step 4:

To a stirred solution of compound2-chloro-6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrimidin-4-amine(0.4 g, 0.68 mmol, 1 eq) in isopropyl alcohol (10 mL) was added2-methoxyaniline (0.146 g, 1.36 mmol, 2.0 eq) at room temperature andheated to 100° C. for 16 h. After completion of the reaction, thereaction mixture was allowed to cool to room temperature. Solvent wasconcentrated under reduced pressure to get crude. The crude was dilutedwith water and the aqueous layer was extracted twice with ethyl acetate,dried over anhydrous sodium sulfate and solvent was evaporated underreduced pressure to get crude compound. The crude was purified byreverse phase preparative HPLC to get 0.04 g of the pure compound(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-N²-(2-methoxyphenyl)pyrimidine-2,4-diamine) as brown solid (yield: 15% over 2 steps).

HPLC-MS [M+H]⁺: 362.39; Rt=2.83 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.52-8.50 (m, 1H), 7.30 (s, 1H), 7.11-7.08(m, 3H), 7.04-7.03 (m, 1H), 6.99-6.97 (m, 1H), 6.89-6.87 (m, 2H), 6.61(br, s, 2H), 6.13 (s, 1H), 3.86 (s, 3H), 3.62 (s, 2H), 3.47 (s, 2H),2.86-2.84 (s, J=4 Hz, 2H), 2.76-2.75 (t, J=4 Hz, 2H).

Intermediate 31 2-((Benzyl(methyl)amino)methyl)-6-chloropyridin-4-amine

Step 1:

50% Propylphosphonic anhydride solution in ethyl acetate (20 mL, 31.5mmol) was added to a suspension of 4,6-dichloropicolinic acid (3 g, 15.7mmol; Intermediate 28), N-methyl-1-phenylmethanamine (2.8 g, 23.6 mmol)and diisopropylethylamine (13.5 mL, 78.9 mmol) in dichloromethane (50mL) at 0° C. The reaction mixture was warmed to room temperature andstirred for 16 h. The reaction mixture was quenched with saturatedsodium bicarbonate solution, the organic product was extracted withdichloromethane (3×40 mL). The combined organic extracts were washedwith water, brine, dried over anhydrous sodium sulfate and solvent wasevaporated under reduced pressure to get crude product. The crudeproduct was purified by flash column chromatography (30% ethylacetate/petroleum ether) to afford 3.5 g ofN-benzyl-4,6-dichloro-N-methylpicolinamide as pale yellow oil (yield:75%; Intermediate 29).

HPLC-MS [M+H]⁺: 295.1; Rt=1.99 min (Method B).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.93-7.90 (m, 1H), 7.85-7.80 (m, 1H),7.40-7.27 (m, 5H), 4.67 (s, 1H), 4.49 (s, 1H), 2.84 (d, J=14 Hz, 3H).

Step 2:

Borane dimethyl sulphide complex solution (33.2 mL, 66.4 mmol; 2.0 M intetrahydrofuran) was added to the solution ofN-benzyl-4,6-dichloro-N-methylpicolinamide (3.1 g, 11.0 mmol) intetrahydrofuran (70 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 16 h. The reaction mixture was cooled to 0°C. and quenched with saturated sodium bicarbonate solution. The organicproduct was extracted with dichloromethane (3×60 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by flash columnchromatography (10% ethyl acetate/petroleum ether) to get 2.1 g ofN-benzyl-4,6-dichloro-N-methylpicolinamide as yellow oil (yield: 71%;Intermediate 30).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.85 (d, J=1.6 Hz, 1H), 7.73 (d, J=2 Hz,1H), 7.66-7.58 (m, 2H), 7.42-7.33 (m, 3H), 4.03-3.99 (m, 2H), 3.78 (d,J=12.4 Hz, 1H), 3.62-3.57 (m, 1H), 2.47 (s, 3H).

Step 3:

Sodium azide (1.38 g, 21.3 mmol) was added to a solution ofN-benzyl-1-(4,6-dichloropyridin-2-yl)-N-methylmethanamine (2 g, 7.1mmol) in anhydrous dimethylformamide (50 mL) at 0° C. The reactionmixture was warmed to room temperature and heated at 90° C. for 24 h.After completion of reaction (monitored by TLC), reaction mixture wasquenched with water and organic product was extracted using ethylacetate (3×50 mL). The combined organic extracts were washed with water,brine, dried over anhydrous sodium sulfate and solvent was evaporatedunder reduced pressure to get crude product. The crude product wasdissolved in methanol (50 mL) and sodium borohydride (0.5 g, 14.2 mmol)was added at 0° C. The reaction mixture was warmed to room temperatureand stirred for 2 h. After completion of reaction, solvent wasevaporated under reduced pressure to obtain residue which was dilutedwith water and extracted using ethyl acetate (3×60 mL). The combinedorganic extracts were washed with water, brine, dried over anhydroussodium sulfate and solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by flash columnchromatography (70% ethyl acetate/petroleum ether) to get 1 g of2-((benzyl(methyl)amino)methyl)-6-chloropyridin-4-amine as yellow oil(yield: 53%).

HPLC-MS [M+H]⁺: 262.1; Rt=1.44 min (Method B).

¹H NMR (400 MHz, CDCl₃) δ: 7.37-7.30 (m, 5H), 7.24-7.22 (m, 1H), 6.74(d, J=2.0 Hz 1H), 6.42 (d, J=2.0 Hz, 1H), 4.22 (br s, 2H), 3.58 (s, 2H),3.54 (s, H), 2.23 (s, 3H).

Biological Assays

Compounds of the Disclosure are capable of binding allosterically tomutated β-glucocerebrosidase enzyme thereby stabilizing the enzymeagainst denaturation and enhancing its catalytic activity.

Enhancement of β-Glucocerebrosidase Activity Measured in Gaucher DiseaseFibroblasts Materials

Human fibroblasts from a patient with Gaucher disease homozygous forp.L444P mutation (GM08760A) were purchased from Coriell Institute forMedical Research (Camden, N.J., USA).

Cell Culture and Compound Treatment

Fibroblasts were seeded at 5×10³ cells per well in 96-well cell cultureplates (Corning, N.Y., USA) in Dulbecco's Modified Eagle's Media (DMEM)supplemented with 10% of fetal bovine serum (FBS), 1%penicillin/streptomycin (P/S) (Thermo Fisher Scientific, Waltham, Mass.,USA) and grown at 37° C., 5% CO₂ overnight for cell attachment.Subsequently, cells were incubated in the absence or presence of thecompounds at the desired concentration for 4 days. After incubation,cells were washed twice with phosphate-buffered saline (PBS) and enzymeactivity assay was performed.

Enzyme Activity Assay

β-glucocerebrosidase activity in intact cultured cells was measured byusing 4-methylumbelliferyl-β-D-glucopyranoside substrate (ApolloScientific, UK). Briefly, cells were incubated with4-MU-β-D-glucopyranoside in 0.1 M acetate buffer pH=4 at 37° C. for 1hour. The reaction was stopped by adding 200 mM glycine-NaOH pH=10.7.The liberated 4-MU was measured on a GloMax Discover plate reader(Promega, Madison, Wis., USA) with and excitation at 340 nm and emissionat 460 nm. Enzyme activities were expressed in treated cells as X-foldincrease in comparison with non-treated cells (X=1 represents noenhancement).

The capacity of the compounds of the disclosure to produce an increasein enzyme activity in GBA fibroblasts bearing L444P at concentrationsbetween 6 and 50 μM is denoted as follows:

Increase in comparison with non-treated of >2.0 fold is shown as A

Increase in comparison with non-treated of >1.7-2.0 fold is shown as B

Increase in comparison with non-treated of 1.2-1.7 fold is shown as C

D means that no increase compared with non-treated cells was detected inthis method

ND means “not determined”

TABLE 1 Example Activity L444P Activity Wild Type (WT) 1 C B 2 C ND 3 CB 4 C A 5 C C 6 B B 7 B B 8 B B 9 C B 10 C B 11 C ND 12 C B 13 B B 14 CB 15 B ND 16 B A 17 B ND 18 B B 19 B B 20 B B 21 B ND 22 B D 23 B ND 24D ND 25 ND ND 26 C B 27 C ND 28 B B 29 B ND 30 A B 31 D A 32 C ND 33 B B34 B ND 35 B ND 36 D ND 37 C B 38 B ND 39 C ND 40 B ND 41 B C 42 C B 43C C 44 B C 45 C C 46 B B 47 C C 48 C B 49 C ND 50 C C 51 C ND 52 C C 53C ND 54 ND ND 55 B ND 56 ND ND 57 C ND 58 ND ND 59 D ND 60 C ND 61 C ND62 D ND 63 C ND 64 B B 65 B A 66 B ND 67 A B 68 B A 69 A C 70 A B 71 CND

Enzyme Activity Assay for Commercially Available Compounds

The following compounds listed in Table 2 were purchased (from Enamine,Princeton, Asinex, Vistas-M, and OSSK_541352) and tested in the assay asdescribed above.

TABLE 2 Activity Activity Compound Structure Name L444P WT

6-((methyl(naphthalen-2- yl)amino)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4-diamine A C

6-((4-(benzo[d][1,3]dioxo1-5- ylmethyl)piperazin-1-yl)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4- diamine C B

6-(((4- ethylbenzyl)(methyl)amino)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4- diamine C B

6-(((furan-2- ylmethyl)(methyl)amino)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4- diamine C ND

6-(indolin-1-ylmethyl)-N2-(p-tolyl)- 1,3,5-triazine-2,4-diamine D D

6-(morpholinomethyl)-N2-(p-tolyl)- 1,3,5-triazine-2,4-diamine D ND

6-((3,4-dihydroquinolin-1(2H)- yl)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4-diamine C C

ethyl 4-((4-amino-6-((4- ethylphenyl)amino)-1,3,5-triazin-2-yl)methyl)piperazine-1-carboxylate D ND

6-((4-phenylpiperazin-1-yl)methyl)- N2-(p-tolyl)-1,3,5-triazine-2,4-diamine C ND

6-((3,4-dihydroisoquinolin-2(1H)- yl)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4-diamine B B

6-((4-methylpiperazin-1-yl)methyl)- N2-(p-tolyl)-1,3,5-triazine-2,4-diamine D ND

6-((4-(3-methoxyphenyl)piperazin- 1-yl)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4-diamine C ND

N2-(4-chlorophenyl)-6-(((3- fluorobenzyl)(methyl)amino)methyl)-1,3,5-triazine-2,4-diamine C ND

6-((methyl(4- methylbenzyl)amino)methyl)-N2-(o-tolyl)-1,3,5-triazine-2,4-diamine C ND

6-((cyclopropyl(4- fluorobenzyl)amino)methyl)-N2-(4-fluorophenyl)-1,3,5-triazine-2,4- diamine C ND

6- ((benzyl(isopropyl)amino)methyl)- N2-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine D ND

6-(1-(benzyl(ethyl)amino)ethyl)-N2- phenyl-1,3,5-triazine-2,4-diamine BB

3-((((4-amino-6-((2- methoxyphenyl)amino)-1,3,5-triazin-2-yl)methyl)(methyl) amino)methyl)benzonitrile D ND

3-((((4-amino-6-((4- fluorophenyl)amino)-1,3,5-triazin-2-yl)methyl)(methyl)amino)methyl) benzonitrile D ND

N2-(4-fluorophenyl)-6-(isoindolin- 2-ylmethyl)-1,3,5-triazine-2,4-diamine B C

N2-(4-fluorophenyl)-6-((2- phenylpyrrolidin-1-yl)methyl)-1,3,5-triazine-2,4-diamine B ND

6-((methyl(phenyl)amino)methyl)- N2-(o-tolyl)-1,3,5-triazine-2,4-diamine C ND

6-(((2-(4-chlorophenoxy) ethyl)(methyl)amino)methyl)-N2-(p-tolyl)-1,3,5-triazine- 2,4-diamine C ND

N2-(2-methoxyphenyl)-6- ((methyl(naphthalen-2-ylmethyl)amino)methyl)-1,3,5- triazine-2,4-diamine B ND

6-((4-(3-chlorophenyl)piperazin-1- yl)methyl)-N2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 1,3,5-triazine-2,4-diamine B C

N2-benzyl-6-((4-(3- methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4- diamine C C

N2-benzyl-6-((4-benzylpiperazin-1- yl)methyl)-1,3,5-triazine-2,4-diamine D ND

N2-(4-chlorobenzyl)-6-((4-(4- fluorophenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4- diamine D ND

The disclosure also relates to the following particular embodimentsdesignated as [1] for the first embodiment, [2] for the secondembodiment, and so on:

[1] A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

with the proviso that no more than two of A¹, A², or A³ is N;

each R⁴ is independently selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring; and

R² is hydrogen or C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl, and—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkylor heterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

[2] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A¹ is N and A² and A³ are each independentlyselected from the group consisting of CH and C(R⁴).[3] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A² is N and A¹ and A³ are each independentlyselected from the group consisting of CH and C(R⁴).[4] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A³ is N and A¹ and A² are each independentlyselected from the group consisting of CH and C(R⁴).[5] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A¹ and A² are both N and A³ is CH or C(R⁴).[6] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A¹ and A³ are both N and A² is CH or C(R⁴).[7] The compound of [1], or a pharmaceutically acceptable salt orsolvate thereof, wherein A² and A³ are both N and A¹ is CH or C(R⁴).[8] The compound of any one of [1] to [7], or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1.[9] The compound of any one of [1] to [7], or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 2.[10] The compound of any one of [1] to [9], or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is unsubstituted C₆₋₁₀aryl or C₆₋₁₀ aryl substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), andC₁₋₄ alkyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, CN,—O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄ alkyl).[11] The compound of any one of [1] to [10], or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is H.[12] The compound of any one of [1] to [10], or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is C₁₋₄ alkyl.[13] The compound of any one of [1] to [10] or [12], or apharmaceutically acceptable salt or solvate thereof, wherein R² ismethyl.[14] The compound of any one of [1] to [13], or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ is —C₆₋₁₀ aryl or —C₁₋₄alkyl-C₆₋₁₀ aryl, wherein said aryl or alkylaryl is optionallysubstituted with 1, 2 or 3 groups each independently selected from thegroup consisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl, wherein Rb is as defined in claim 1.[15] The compound of any one of [1] to [14], or a pharmaceuticallyacceptable salt or solvate thereof, wherein Rb is hydrogen or C₁₋₄alkyl.[16] The compound of any one of [1] to [10], or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ and R² together with thenitrogen atom to which they are attached form an optionally substituted5- to 10-membered heterocyclic ring, wherein said heterocyclic ringoptionally contains 1, 2, or 3 additional heteroatoms selected from thegroup consisting of N, S, or O, and wherein said heterocyclic ring isoptionally fused to a phenyl ring.[17] The compound of [16], or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ and R² together with the nitrogen atom towhich they are attached form a 5- or 6-membered ring optionally fused toa phenyl ring.[18] The compound of [1], which is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.[19] A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.[20] A pharmaceutical composition, comprising an effective amount of acompound of any one of [1] to [19], or a pharmaceutically acceptablesalt or solvate thereof, and at least one pharmaceutically acceptableexcipient.[21] A method of treating or preventing Gaucher's disease, comprisingadministering to a patient in need thereof an effective amount of acompound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independent selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl, and—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

[22] The method of [21], wherein A¹, A² and A³ are N.[23] The method of [21], wherein the compound administered is as claimedin any one of [1] to [20].[24] The method of [21], wherein the compound administered is selectedfrom the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.[25] A compound as defined in any one of [1] to [20], or apharmaceutically acceptable salt or solvate thereof, for use as amedicament.[26] A compound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, for use in the treatment or prevention of Gaucher'sdisease, the compound of formula (I) having the structure:

wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independently selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl, and—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyl optionallysubstituted with 1, 2, or 3 groups each independently selected from thegroup consisting of halogen, CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

[27] The compound for use of [26], wherein the compound is as claimed inany one of claims 1-20.[28] The compound for use of [26], wherein the compound is selected fromthe group consisting of

or a pharmaceutically acceptable salt or solvate thereof.[29] Use of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, for the manufacture of a medicament for thetreatment or prevention of Gaucher's disease, the compound of formula(I) having the structure:

wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independent selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl, and—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3 groupseach independently selected from the group consisting of halogen,hydroxy, CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionally substituted with1, 2, or 3 groups each independently selected from the group consistingof halogen, CN, —ORb, and —N(Rb)₂, optionally substituted —C₆₋₁₀ aryl,optionally substituted -(5- to 10-membered)-C₁₋₉ heteroaryl and -(5- to10-membered)-C₂₋₉ heterocyclyl.

[30] The use of [29], wherein the compound is as in any one of [1] to[20].[31] The use of [29], wherein the compound is selected from the groupconsisting of

or a pharmaceutically acceptable salt or solvate thereof.[32] A pharmaceutical composition, comprising an effective amount of acompound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, and at leastone pharmaceutically acceptable excipient, for use in the treatment orprevention of Gaucher's disease, wherein

A¹, A², and A³ are each independently selected from the group consistingof N, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N;

each R⁴ is independent selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and CN;

n is 1 or 2;

R¹ is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and

R² is hydrogen or C₁₋₄ alkyl; or

R¹ and R² together with the nitrogen atom to which they are attachedform an optionally substituted 5- to 10-membered heterocyclic ring,wherein said heterocyclic ring optionally contains 1, 2, or 3 additionalheteroatoms selected from the group consisting of N, S, or O, andwherein said heterocyclic ring is optionally fused to a phenyl ring;

Ra is selected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀aryl, (5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to10-membered)-C₁₋₉ heteroaryl, (5- to 10-membered)-C₂₋₉ heterocyclyl, and—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted C₆₋₁₀ aryl, optionally substituted (5- to10-membered)-C₁₋₉ heteroaryl, and (5- to 10-membered)-C₂₋₉ heterocyclyl;and wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl,heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl isoptionally fused to a further (second) ring;

each Rb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms;

R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl, wherein saidaryl or heteroaryl group is optionally substituted with 1, 2 or 3substituents each independently selected from the group consisting ofhalogen, hydroxy, CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.

All publications cited in this specification are incorporated herein byreference. While the disclosure has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the disclosure. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹,A², and A³ are each independently selected from the group consisting ofN, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N; withthe proviso that no more than two of A¹, A², or A³ is N; each R⁴ isindependently selected from the group consisting of halogen, —C₁₋₄alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein the alkylene chaincan be optionally substituted with one or more —C₁₋₄ alkyl groups; R¹ isselected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl,—C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 2. The compound of claim 1,or a pharmaceutically acceptable salt or solvate thereof, wherein A¹,A², and A³ are each independently selected from the group consisting ofN, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N; withthe proviso that no more than two of A¹, A², or A³ is N; each R⁴ isindependently selected from the group consisting of halogen, —C₁₋₄alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2; R¹ is selected from the groupconsisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; and R²is hydrogen or —C₁₋₄ alkyl; or R¹ and R² together with the nitrogen atomto which they are attached form an optionally substituted 5- to10-membered heterocyclic ring, wherein said heterocyclic ring optionallycontains 1, 2, or 3 additional heteroatoms selected from the groupconsisting of N, S, or O, and wherein said heterocyclic ring isoptionally fused to a phenyl ring; Ra is selected from the groupconsisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; R³ is —C₆₋₁₀ aryl or -(5- to 10-membered)-C₁₋₉ heteroaryl,wherein said aryl or heteroaryl group is optionally substituted with 1,2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —ORb, and —N(Rb)₂,optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl.3. The compound of claim 1 or 2, or a pharmaceutically acceptable saltor solvate thereof, wherein A¹ is N and A² and A³ are each independentlyselected from the group consisting of CH and C(R⁴).
 4. The compound ofclaim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,wherein A² is N and A¹ and A³ are each independently selected from thegroup consisting of CH and C(R⁴).
 5. The compound of claim 1 or 2, or apharmaceutically acceptable salt or solvate thereof, wherein A³ is N andA¹ and A² are each independently selected from the group consisting ofCH and C(R⁴).
 6. The compound of claim 1 or 2, or a pharmaceuticallyacceptable salt or solvate thereof, wherein A¹ and A² are both N and A³is CH or C(R⁴).
 7. The compound of claim 1 or 2, or a pharmaceuticallyacceptable salt or solvate thereof, wherein A¹ and A³ are both N and A²is CH or C(R⁴).
 8. The compound of claim 1 or 2, or a pharmaceuticallyacceptable salt or solvate thereof, wherein A² and A³ are both N and A¹is CH or C(R⁴).
 9. The compound of any one of claims 1-8, or apharmaceutically acceptable salt or solvate thereof, wherein n is
 1. 10.The compound of any one of claims 1-8, or a pharmaceutically acceptablesalt or solvate thereof, wherein n is
 2. 11. The compound of any one ofclaims 1-10, or a pharmaceutically acceptable salt or solvate thereof,wherein R³ is unsubstituted —C₆₋₁₀ aryl or —C₆₋₁₀ aryl substituted with1 or 2 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —O(C₁₋₄)alkyl, —S(C₁₋₄)alkyl,—N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ alkyl), and —C₁₋₄ alkyl optionally substitutedwith 1, 2, or 3 substituents each independently selected from the groupconsisting of halogen, —CN, —O(C₁₋₄)alkyl, —N(C₁₋₄ alkyl)₂, and —NH(C₁₋₄alkyl).
 12. The compound of any one of claims 1-11, or apharmaceutically acceptable salt or solvate thereof, wherein R² is H.13. The compound of any one of claims 1-11, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is —C₁₋₄ alkyl.
 14. Thecompound of any one of claims 1-11 or 13, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is methyl.
 15. Thecompound of any one of claims 1-14, or a pharmaceutically acceptablesalt or solvate thereof, wherein R¹ is —C₆₋₁₀ aryl or —C₁₋₄ alkyl-C₆₋₁₀aryl, wherein said aryl or alkylaryl is optionally substituted with 1, 2or 3 groups each independently selected from the group consisting ofhalogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyl optionallysubstituted with 1, 2, or 3 halogen atoms, optionally substituted —C₆₋₁₀aryl, optionally substituted -(5- to 10-membered)-C₁₋₉ heteroaryl, and-(5- to 10-membered)-C₂₋₉ heterocyclyl, wherein Rb is as defined inclaim
 1. 16. The compound of any one of claims 1-15, or apharmaceutically acceptable salt or solvate thereof, wherein Rb ishydrogen or —C₁₋₄ alkyl.
 17. The compound of any one of claims 1-11, ora pharmaceutically acceptable salt or solvate thereof, wherein R¹ and R²together with the nitrogen atom to which they are attached form anoptionally substituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring.
 18. The compoundof claim 17, or a pharmaceutically acceptable salt or solvate thereof,wherein R¹ and R² together with the nitrogen atom to which they areattached form a 5- or 6-membered ring optionally fused to a phenyl ring.19. The compound of claim 1, which is selected from the group consistingof

or a pharmaceutically acceptable salt or solvate thereof.
 20. Thecompound of claim 1, which is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 21. A compoundselected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 22. A compoundselected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 23. Apharmaceutical composition, comprising an effective amount of a compoundof any one of claims 1-22, or a pharmaceutically acceptable salt orsolvate thereof, and at least one pharmaceutically acceptable excipient.24. A method of treating or preventing a lysosomal storage disease,comprising administering to a patient in need thereof an effectiveamount of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹,A², and A³ are each independently selected from the group consisting ofN, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N; eachR⁴ is independent selected from the group consisting of halogen, —C₁₋₄alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein the alkylene chaincan be optionally substituted with one or more —C₁₋₄ alkyl groups; R¹ isselected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl,—C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 25. The method of claim 24,wherein the lysosomal storage disease is Gaucher's disease.
 26. Themethod of claim 24 or 25, wherein A¹, A² and A³ are N.
 27. The method ofclaim 24 or 25, wherein the compound administered is as claimed in anyone of claims 1-22.
 28. The method of claim 24 or 25, wherein thecompound administered is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 29. The methodof claim 24 or 25, wherein the compound administered is selected fromthe group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 30. The methodof any one of claims 24-29, further comprising administering to thepatient at least one other therapeutic agent.
 31. The method of claim30, wherein the therapeutic agent is an effective amount of an enzymefor enzyme replacement therapy.
 32. The method of claim 31, wherein theenzyme is β-glucocerebrosidase or an analog thereof.
 33. The method ofclaim 32, wherein the enzyme is imiglucerase.
 34. The method of any oneof claims 30-33, wherein the therapeutic agent is an effective amount ofa small molecule chaperone.
 35. The method of claim 34, wherein thesmall molecule chaperone binds competitively to an enzyme.
 36. Themethod of claim 34 or 35, wherein the small molecule chaperone isselected from the group consisting of iminoalditols, iminosugars,aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyltransferase, phosphatase, and peptidase inhibitors.
 37. The method ofclaim 36, wherein the small molecule chaperone is selected from thegroup consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat.
 38. A compound as defined in any one of claims1-22, or a pharmaceutically acceptable salt or solvate thereof, for useas a medicament.
 39. A compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment orprevention of lysosomal storage disease, the compound of formula (I)having the structure:

wherein A¹, A², and A³ are each independently selected from the groupconsisting of N, CH and C(R⁴), provided that at least one of A¹, A², orA³ is N; each R⁴ is independently selected from the group consisting ofhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein thealkylene chain can be optionally substituted with one or more —C₁₋₄alkyl groups; R¹ is selected from the group consisting of —C₁₋₄ alkyl,—C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄alkyl-C₆₋₁₀ aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 40. The compound for use asclaimed in claim 39, wherein said use is for the treatment or preventionof Gaucher's disease.
 41. The compound for use as claimed in claim 39 or40, wherein the compound is as claimed in any one of claims 1-22. 42.The compound for use as claimed in claim 39 or 40, wherein the compoundis selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 43. Thecompound for use as claimed in claim 39 or 40, wherein the compound isselected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 44. Use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, for the manufacture of a medicament for the treatmentor prevention of a lysosomal storage disease, the compound of formula(I) having the structure:

wherein A¹, A², and A³ are each independently selected from the groupconsisting of N, CH and C(R⁴), provided that at least one of A¹, A², orA³ is N; each R⁴ is independent selected from the group consisting ofhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein thealkylene chain can be optionally substituted with one or more —C₁₋₄alkyl groups; R¹ is selected from the group consisting of —C₁₋₄ alkyl,—C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄alkyl-C₆₋₁₀ aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 45. Use as claimed in claim44, wherein the manufacture is for a treatment or prevention ofGaucher's disease.
 46. The use as claimed in claim 44 or 45, wherein thecompound is as claimed in any one of claims 1-22.
 47. The use as claimedin claim 44 or 45, wherein the compound is selected from the groupconsisting of

or a pharmaceutically acceptable salt or solvate thereof.
 48. The use asclaimed in claim 44 or 45, wherein the compound is selected from thegroup consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 49. Apharmaceutical composition, comprising an effective amount of a compoundof formula (I):

or a pharmaceutically acceptable salt or solvate thereof, and at leastone pharmaceutically acceptable excipient, for use in the treatment orprevention of a lysosomal storage disease, wherein A¹, A², and A³ areeach independently selected from the group consisting of N, CH andC(R⁴), provided that at least one of A¹, A², or A³ is N; each R⁴ isindependent selected from the group consisting of halogen, —C₁₋₄ alkyl,—C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein the alkylene chain can beoptionally substituted with one or more —C₁₋₄ alkyl groups; R¹ isselected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl,—C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 50. The pharmaceuticalcomposition of claim 49, for use in the treatment or prevention ofGaucher's disease.
 51. A method of treating or preventing a disease ordisorder selected from the group consisting of Parkinson's disease, Lewybody disease, dementia, multiple system atrophy, epilepsy, bipolardisorder, schizophrenia, an anxiety disorder, major depression,polycyctic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, and multiple myeloma, comprising administering to apatient in need thereof an effective amount of a compound of formula(I):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹,A², and A³ are each independently selected from the group consisting ofN, CH and C(R⁴), provided that at least one of A¹, A², or A³ is N; eachR⁴ is independent selected from the group consisting of halogen, —C₁₋₄alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein the alkylene chaincan be optionally substituted with one or more —C₁₋₄ alkyl groups; R¹ isselected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl,—C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₄ alkyl is optionallysubstituted with —O(C₁₋₄)alkyl optionally substituted with —O(C₁₋₄)NH₂,hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² together with thenitrogen atom to which they are attached form an optionally substituted5- to 10-membered heterocyclic ring, wherein said heterocyclic ringoptionally contains 1, 2, or 3 additional heteroatoms selected from thegroup consisting of N, S, or O, and wherein said heterocyclic ring isoptionally fused to a phenyl ring; Ra is selected from the groupconsisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 52. The method of claim 51,wherein the disease is Parkinson's disease.
 53. The method of claim 51or 52, wherein A¹, A² and A³ are N.
 54. The method of claim 51 or 52,wherein the compound administered is as claimed in any one of claims1-22.
 55. The method of claim 51 or 52, wherein the compoundadministered is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 56. The methodof claim 51 or 52, wherein the compound administered is selected fromthe group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 57. The methodof any one of claims 51-56, further comprising administering to thepatient at least one other therapeutic agent.
 58. The method of claim57, wherein the therapeutic agent is an effective amount of an enzymefor enzyme replacement therapy.
 59. The method of claim 58, wherein theenzyme is β-glucocerebrosidase or an analog thereof.
 60. The method ofclaim 59, wherein the enzyme is imiglucerase.
 61. The method of any oneof claims 57-60, wherein the therapeutic agent is an effective amount ofa small molecule chaperone.
 62. The method of claim 61, wherein thesmall molecule chaperone binds competitively to an enzyme.
 63. Themethod of claim 61 or 62, wherein the small molecule chaperone isselected from the group consisting of iminoalditols, iminosugars,aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyltransferase, phosphatase, and peptidase inhibitors.
 64. The method ofclaim 63, wherein the small molecule chaperone is selected from thegroup consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ),ambroxol, and miglustat.
 65. A compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, for use in thetreatment or prevention of a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma, thecompound of formula (I) having the structure:

wherein A¹, A², and A³ are each independently selected from the groupconsisting of N, CH and C(R⁴), provided that at least one of A¹, A², orA³ is N; each R⁴ is independently selected from the group consisting ofhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein thealkylene chain can be optionally substituted with one or more —C₁₋₄alkyl groups; R¹ is selected from the group consisting of —C₁₋₄ alkyl,—C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄alkyl-C₆₋₁₀ aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 66. The compound for use asclaimed in claim 65, wherein said use is for the treatment or preventionof Parkinson's disease.
 67. The compound for use as claimed in claim 65or 66, wherein the compound is as claimed in any one of claims 1-22. 68.The compound for use as claimed in claim 65 or 66, wherein A¹, A² and A³are N.
 69. The compound for use as claimed in claim 65 or 66, whereinthe compound is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 70. Thecompound for use as claimed in claim 65 or 66, wherein the compound isselected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 71. Use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, for the manufacture of a medicament for the treatmentor prevention of a disease or disorder selected from the groupconsisting of Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycyctic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, and multiple myeloma, thecompound of formula (I) having the structure:

wherein A¹, A², and A³ are each independently selected from the groupconsisting of N, CH and C(R⁴), provided that at least one of A¹, A², orA³ is N; each R⁴ is independent selected from the group consisting ofhalogen, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein thealkylene chain can be optionally substituted with one or more —C₁₋₄alkyl groups; R¹ is selected from the group consisting of —C₁₋₄ alkyl,—C₃₋₁₀ cycloalkyl, —C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄alkyl-C₆₋₁₀ aryl, -(5- to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,—C₁₋₄ alkyl-(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, whereinsaid alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 72. Use as claimed in claim71, wherein the manufacture is for a treatment or prevention ofParkinson's disease.
 73. The use as claimed in claim 71 or 72, whereinthe compound is as claimed in any one of claims 1-22.
 74. The use asclaimed in claim 71 or 72, wherein A¹, A² and A³ are N.
 75. The use asclaimed in claim 71 or 72, wherein the compound is selected from thegroup consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 76. The use asclaimed in claim 71 or 72, wherein the compound is selected from thegroup consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 77. Apharmaceutical composition, comprising an effective amount of a compoundof formula (I):

or a pharmaceutically acceptable salt or solvate thereof, and at leastone pharmaceutically acceptable excipient, for use in the treatment orprevention of a disease or disorder selected from the group consistingof Parkinson's disease, Lewy body disease, dementia, multiple systematrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder,major depression, polycyctic kidney disease, type 2 diabetes, open angleglaucoma, multiple sclerosis, and multiple myeloma, wherein A¹, A², andA³ are each independently selected from the group consisting of N, CHand C(R⁴), provided that at least one of A¹, A², or A³ is N; each R⁴ isindependent selected from the group consisting of halogen, —C₁₋₄ alkyl,—C₁₋₄ alkoxy, and —CN; n is 1 or 2, wherein the alkylene chain can beoptionally substituted with one or more —C₁₋₄ alkyl groups; R¹ isselected from the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl,—C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, —C₁₋₄ alkyl-(5- to10-membered)-C₂₋₉ heterocyclyl, and —C(═O)Ra, wherein said alkyl,cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups areoptionally substituted with 1, 2 or 3 substituents each independentlyselected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb,—N(Rb)₂, —C₁₋₄ alkyl optionally substituted with 1, 2, or 3 halogenatoms, optionally substituted —C₆₋₁₀ aryl, optionally substituted -(5-to 10-membered)-C₁₋₉ heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl,optionally substituted —O—(C₆₋₁₀ aryl); and wherein said cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl is optionally fused to a further(second) ring; and R² is selected from the group consisting of hydrogen,—C₁₋₄ alkyl, and —C₃₋₆ cycloalkyl, wherein said —C₁₋₄ alkyl isoptionally substituted with —O(C₁₋₄)alkyl optionally substituted with—O(C₁₋₄)NH₂, hydroxy, —CN, halogen, or —N(Rb)₂; or R¹ and R² togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 10-membered heterocyclic ring, wherein saidheterocyclic ring optionally contains 1, 2, or 3 additional heteroatomsselected from the group consisting of N, S, or O, and wherein saidheterocyclic ring is optionally fused to a phenyl ring; Ra is selectedfrom the group consisting of —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₄alkyl-C₃₋₁₀ cycloalkyl, —C₆₋₁₀ aryl, —C₁₋₄ alkyl-C₆₋₁₀ aryl, (5- to10-membered)-C₁₋₉ heteroaryl, —C₁₋₄ alkyl-(5- to 10-membered)-C₁₋₉heteroaryl, -(5- to 10-membered)-C₂₋₉ heterocyclyl, and —C₁₋₄ alkyl-(5-to 10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl,alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl,heterocyclyl and alkylheterocyclyl groups are optionally substitutedwith 1, 2 or 3 substituents each independently selected from the groupconsisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄ alkyloptionally substituted with 1, 2, or 3 halogen atoms, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl, and -(5- to 10-membered)-C₂₋₉heterocyclyl; and wherein said cycloalkyl, alkylcycloalkyl, aryl,alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl andalkylheterocyclyl is optionally fused to a further (second) ring; eachRb is independently hydrogen, —C₁₋₄ alkyl, —C₃₋₁₀ cycloalkyl, or -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said alkyl, cycloalkyl orheterocyclyl group is optionally substituted by 1, 2 or 3 fluorineatoms; and R³ is selected from the group consisting of —C₆₋₁₀ aryl, -(5-to 10-membered)-C₁₋₉ heteroaryl, —C₃₋₁₀ cycloalkyl, and -(5- to10-membered)-C₂₋₉ heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl, and heterocyclyl groups are optionally substituted with 1, 2or 3 substituents each independently selected from the group consistingof halogen, hydroxy, CN, —ORb, —SRb, —N(Rb)₂, —C₁₋₄alkyl optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —ORb, and —N(Rb)₂, optionallysubstituted —C₆₋₁₀ aryl, optionally substituted -(5- to10-membered)-C₁₋₉ heteroaryl and -(5- to 10-membered)-C₂₋₉ heterocyclyl,and wherein said aryl, heteroaryl, cycloalkyl, and heterocyclyl isoptionally fused to a further (second) ring.
 78. The pharmaceuticalcomposition of claim 77, for use in the treatment or prevention ofParkinson's disease.